Edit­ing genes could erase dis­ease — or weaponize it

Book re­view by Jerry A. Coyne

The Washington Post Sunday - - OUTLOOK - Jerry A. Coyne is pro­fes­sor emer­i­tus in the Depart­ment of Ecol­ogy and Evo­lu­tion at the Univer­sity of Chicago. He is the author of “Why Evo­lu­tion Is True” and “Faith vs. Fact: Why Sci­ence and Re­li­gion Are In­com­pat­i­ble.”

Some of the great­est bene­fac­tors of our species are not the rec­og­nized do-good­ers but those paid to sat­isfy their cu­rios­ity: the sci­en­tists. Such pure and un­sul­lied in­quiry has yielded thou­sands of valu­able byprod­ucts, in­clud­ing an­tibi­otics, vac­ci­na­tions, X-rays and in­sulin ther­apy.

Jen­nifer Doudna and Sa­muel Stern­berg’s “A Crack in Cre­ation” de­scribes an­other for­tu­itous dis­cov­ery: a method that prom­ises to rev­o­lu­tion­ize biotech­nol­ogy by al­low­ing us to change nearly any gene in any way in any species. The method is called CRISPR, pro­nounced like the use­less com­part­ment in your fridge. In terms of sci­en­tific im­pact, CRISPR is right up there be­side the dou­ble helix (1953); the abil­ity, de­vel­oped in the 1970s, to de­ter­mine the se­quence of DNA seg­ments; and the poly­merase chain re­ac­tion, a 1980s in­ven­tion that al­lows us to am­plify spec­i­fied sec­tions of DNA. All three achieve­ments were rec­og­nized with No­bel Prizes. CRISPR — de­vel­oped largely by Doudna and her French col­league Em­manuelle Char­p­en­tier — also has a

strong whiff of No­bel about it, for its med­i­cal and prac­ti­cal im­pli­ca­tions are im­mense.

The story of CRISPR is told with re­fresh­ing first-per­son di­rect­ness in this book. (Stern­berg was Doudna’s stu­dent, but the book uses Doudna’s voice.) It is not of­ten in sci­ence writ­ing that the ac­tual dis­cov­erer puts pen to pa­per — rather, the story is usu­ally told by a sci­ence writer or col­league — so this in­sider ac­count is es­pe­cially en­gag­ing.

CRISPR, an acro­nym for “clus­tered reg­u­larly in­ter­spaced short palin­dromic re­peats,” is a way to edit DNA. With CRISPR, we can change a se­quence from ATTGGCG to ATTGGGG or to CCCCCCC, or to any­thing else. There are other re­cently de­vel­oped ways to do this, but they are uni­formly un­wieldy, time-con­sum­ing and in­ef­fi­cient. The joy of CRISPR is that it al­lows us to edit genes pain­lessly: It is eas­ily ap­plied and seems to work well in what­ever species or cell type we choose.

The his­tory of CRISPR is a prime ex­am­ple of the un­ex­pected ben­e­fits of pure re­search, for it be­gan with a hand­ful of cu­ri­ous sci­en­tists not in­tent on chang­ing the world. In the late 1980s, sci­en­tists ob­served a bizarre sec­tion of DNA in some bac­te­ria, con­sist­ing of short, iden­ti­cal and re­peated “palin­dromic” se­quences that read the same way back­ward and for­ward (e.g., CATGTTGTAC). The re­peated palin­dromes were sep­a­rated by 20-let­ter seg­ments of unique DNA, seg­ments even­tu­ally found to come from viruses that in­fect bac­te­ria. Peo­ple soon re­al­ized that the CRISPR re­gion was the bac­terium’s im­mune sys­tem against dan­ger­ous viruses.

CRISPR helps bac­te­ria “re­mem­ber” pre­vi­ous viral at­tacks and thus pre­pares them for fu­ture at­tacks by the same virus. This is anal­o­gous to our im­mune sys­tem, which also “re­mem­bers” in­trud­ers: If you have had measles once, you won’t get it again be­cause the first ex­po­sure preps the im­mune sys­tem for subse- quent ex­po­sures. The way bac­te­ria do this is by stor­ing a seg­ment of the virus’s DNA from the first at­tack. When the same kind of virus strikes again, the bac­terium rec­og­nizes that the alien DNA seg­ment has reap­peared by match­ing the stored seg­ment to the in­truder DNA. Hav­ing iden­ti­fied the in­truder as a bad guy, the bac­terium can snip up, i.e., de­stroy, the in­truder’s DNA, guided by the same stored-DNA/in­truder-DNA match.

Doudna and Char­p­en­tier re­al­ized that it was pos­si­ble to sub­vert the CRISPR sys­tem: In­stead of viral in­truder DNA, we can use the DNA se­quence we’re in­ter­ested in (say, one caus­ing a ge­netic dis­ease), with the re­sult that CRISPR snips up any and all DNA mol­e­cules with the tar­get se­quence. Once DNA is snipped up, there are ways to re­pair it us­ing a dif­fer­ent se­quence, in­clud­ing a ver­sion of the gene that does not pro­duce dis­ease. Presto: gene edit­ing and a path to de­signer genes.

Rewrit­ing genes has the po­ten­tial to cure many ge­netic ill­nesses. Peo­ple suf­fer­ing from sickle-cell dis­ease, for in­stance, have just a sin­gle mu­tated “let­ter” in the DNA cod­ing for their he­mo­glo­bin. It shouldn’t be hard for CRISPR to re­place that let­ter in em­bryos or bone mar­row, cur­ing the mil­lions who suf­fer from this dev­as­tat­ing mal­ady.

But that’s just one of myr­iad pos­si­ble ed­its. CRISPR can in the­ory cure any dis­ease caused by one or a few mu­ta­tions: not just sickle-cell but Hunt­ing­ton’s dis­ease, cys­tic fi­bro­sis, mus­cu­lar dys­tro­phy or color blind­ness. We could cure AIDS pa­tients by edit­ing out the HIV viruses that hide in their DNA. By edit­ing early em­bryos, we could re­duce the in­ci­dence of ge­net­i­cally in­flu­enced dis­eases such as Alzheimer’s and some types of breast cancer. We could make cos­metic changes in our chil­dren, al­ter­ing their hair and eye color or even, in prin­ci­ple, their height, weight, body shape and in­tel­li­gence. None of this has been tried in peo­ple, but since CRISPR works well in hu­man cell cul­tures, it seems just a mat­ter of time.

Turn­ing to other species, we could ge­net­i­cally en­gi­neer ei­ther pigs or peo­ple so we could trans­plant pig or­gans into hu­mans with­out ac­ti­vat­ing our im­mune re­sponse. We’ve used CRISPR to make virus-re­sis­tant farm an­i­mals, and we can now en­gi­neer in­sec­ti­cide-mak­ing genes into the DNA of crops, elim­i­nat­ing the need for dan­ger­ous sprays. As the book ti­tle im­plies, CRISPR al­lows us to by­pass or undo evo­lu­tion with­out re­ly­ing on the hit-or-miss meth­ods of se­lec­tive breed­ing.

But of course DNA edit­ing also raises eth­i­cal is­sues, and th­ese oc­cupy the fi­nal quar­ter of the book. Doudna wor­ries about the re­turn of Nazi-style eu­gen­ics and even had a dream about Hitler ask­ing her for CRISPR tech­nol­ogy. Should we en­gage only in “so­matic” gene edit­ing: chang­ing genes in af­fected tis­sues where they can’t be passed on to the next gen­er­a­tion? Or should we also do “germline” edit­ing, chang­ing early em­bryos in a way that could be trans­mit­ted to fu­ture gen­er­a­tions? While that con­jures up the bad old days of eu­gen­ics, it is in fact the only way to re­pair most “dis­ease genes.” But if we do that, should we stick to fix­ing genes that would de­bil­i­tate the offspring, as with sickle-cell dis­ease, or should we also change genes that merely raise the pos­si­bil­ity of ill­ness: those that could pro­duce high choles­terol or heart dis­ease?

Things get even more slip­pery. Should we edit the em­bryos of deaf par­ents to pro­duce deaf offspring, so that their chil­dren can par­tic­i­pate in “deaf cul­ture”? And — the ul­ti­mate taboo — ge­netic en­hance­ment: Should we give our chil­dren a leg up in looks or in­tel­li­gence? That, af­ter all, will pro­vide ge­netic ad­van­tages only to those who can af­ford the tech­nol­ogy.

Fi­nally, how do we keep the tech­nol­ogy out of the hands of bioter­ror­ists? Cheap and sim­ple CRISPR kits are now sold on the In­ter­net, al­low­ing any­one to edit the genes of bac­te­ria. The night­mar­ish prospect of en­gi­neered dis­eases looms. While it’s good to con­sider all th­ese ques­tions be­fore the tech­nol­ogy is widely avail­able, Doudna and Stern­berg come to few con­clu­sions, and their ex­tended vac­il­lat­ing is the book’s sole flaw.

Along­side the eth­i­cal quan­daries come com­mer­cial ones. There is a great deal of money to be made through the li­cens­ing of CRISPR tech­nol­ogy. We have al­ready seen a pro­tracted patent bat­tle be­tween Doudna’s em­ployer, the Univer­sity of Cal­i­for­nia, and Har­vard/MIT’s Broad In­sti­tute, home to Feng Zhang, who was largely re­spon­si­ble for con­vert­ing CRISPR from a de­vice for edit­ing bac­te­rial genes into a lab-friendly tool that works in hu­man cells. There is a lot at stake.

And this brings us to an is­sue con­spic­u­ously miss­ing from the book. Much of the re­search on CRISPR, in­clud­ing Doudna’s and Zhang’s, was funded by the fed­eral gov­ern­ment — by Amer­i­can tax­pay­ers. Yet both sci­en­tists have started biotech­nol­ogy com­pa­nies that have the po­ten­tial to make them and their uni­ver­si­ties fab­u­lously wealthy from li­cens­ing CRISPR for use in medicine and be­yond. So if we value ethics, trans­parency and the de­moc­ra­ti­za­tion of CRISPR tech­nol­ogy, as do Doudna and Stern­berg, let us also con­sider the ethics of sci­en­tists en­rich­ing them­selves on the tax­payer’s dime. The fight over patents and credit im­pedes the free ex­change among sci­en­tists that pro­motes progress, and com­pa­nies cre­ated from tax­payer-funded re­search make us pay twice to use their prod­ucts.

Fi­nally, let us re­mem­ber that it was not so long ago that univer­sity sci­en­tists re­fused to en­rich them­selves in this way, freely giv­ing dis­cov­er­ies such as X-rays, the po­lio vac­cine and the In­ter­net to the public. The sat­is­fac­tion of sci­en­tific cu­rios­ity should be its pri­mary re­ward.

Jen­nifer Doudna wor­ries about the re­turn of Nazi-style eu­gen­ics and even had a dream about Hitler ask­ing her for CRISPR tech­nol­ogy.

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