This is Why Gene Editing of Plants and Animals Needs to be Regulated

Jonathan R. Latham

Gene editing has many potential uses. There's also a lot that can go wrong.

Gene edit­ing of DNA inside liv­ing cells has many poten­tial uses — from treat­ing human dis­ease to alter­ing crops and live­stock for agri­cul­ture — and is often con­sid­ered the pre­em­i­nent tech­no­log­i­cal break­through of the new mil­len­ni­um. For exam­ple, in a move that has been wide­ly crit­i­cized, Chi­nese researcher He Jiankui claims to have edit­ed human babies to resist HIV by alter­ing a gene called CCR5.

For most com­mer­cial appli­ca­tions gene editing’s appeal is sim­plic­i­ty and pre­ci­sion: It alters genomes at pre­cise sites, with­out insert­ing for­eign DNA. This is why, in pop­u­lar arti­cles, gene edit­ing is often referred to as tweak­ing.”

The tweak­ing nar­ra­tive, how­ev­er, is an assump­tion and not an estab­lished fact. And it recent­ly suf­fered a large dent.

In late July researchers from the US Food and Drug Admin­is­tra­tion (FDA) ana­lyzed the whole genomes of two calves orig­i­nal­ly born in 2016. The calves were edit­ed by the biotech start­up Recom­bi­net­ics and had become biotech celebri­ties for hav­ing a genet­ic change that removed their horns. Cat­tle with­out horns are known as polled.” The calves are well-known because Recom­bi­net­ics has insist­ed that its two edit­ed ani­mals were altered with extreme pre­ci­sion to pos­sess only the polled trait.

How­ev­er, what the FDA researchers found was not pre­ci­sion. Each of Recom­bi­net­ics’ calves pos­sessed two antibi­ot­ic resis­tance genes, along with oth­er seg­ments of super­flu­ous bac­te­r­i­al DNA. Thus, appar­ent­ly unbe­knownst to Recom­bi­net­ics, adja­cent to its edit­ed site were 4,000 base pairs of DNA that were unin­ten­tion­al­ly intro­duced along­side the DNA required for the horn­less trait.

The FDA find­ing has attract­ed some media atten­tion, most of it focused on the incom­pe­tence of Recom­bi­net­ics. The start­up failed to find (or per­haps look for) this DNA, which it had itself added as part of the edit­ing process. Fol­low­ing the FDA find­ings, Brazil ter­mi­nat­ed a breed­ing pro­gram begun with the Recom­bi­net­ics animals.

The FDA’s find­ings in this case, how­ev­er, pale in com­par­i­son to anoth­er recent dis­cov­ery about gene edit­ing: that for­eign DNA from sur­pris­ing sources can rou­tine­ly find its way into the genome of edit­ed animals.

These find­ings have not been report­ed in the sci­en­tif­ic or pop­u­lar media. But they are of great con­se­quence from a biosafe­ty per­spec­tive: They show the need for strong reg­u­la­to­ry over­sight of the gene-edit­ing industry.

Impli­ca­tions of super­flu­ous DNA in edit­ed cells

In short, the new find­ings are very sim­ple: Cut­ting DNA inside cells, regard­less of the pre­cise type of gene edit­ing, pre­dis­pos­es genomes to acquire unwant­ed DNA. There­fore, it is not hard to imag­ine, for instance, gene-edit­ed ani­mals becom­ing the breed­ing stock that leads to the devel­op­ment or spread of nov­el or unwel­come virus­es or mycoplas­mas. This is because they make take up DNA from oth­er species that con­t­a­m­i­nates the edit­ing reagents.

Stu­art New­man of New York Med­ical Col­lege is a cell biol­o­gist, a found­ing mem­ber of the Coun­cil for Respon­si­ble Genet­ics, and Edi­tor-In-Chief of the jour­nal Bio­log­i­cal The­o­ry.

I have lit­tle doubt E. coli DNA has been inad­ver­tent­ly incor­po­rat­ed into many CRISPR tar­gets,” New­man said, refer­ring to a method of gene edit­ing. And it is like­ly to cause prob­lems, as it has in the horned cattle.”

Sim­i­lar wor­ries apply to human appli­ca­tions. Con­cern over the incor­po­ra­tion of DNA from oth­er species has not been raised pub­licly in con­nec­tion with the gene-edit­ed human babies of researcher He Jiankui, but, clear­ly, it should be.

The sec­ond impor­tant con­clu­sion, and what the Recom­bi­net­ics case exem­pli­fies, is that researchers are often not look­ing for stray DNA. If they were to look, many more exam­ples would like­ly be report­ed. We can con­clude this because the research cit­ed above used stan­dard meth­ods of gene edit­ing. The only atyp­i­cal aspect was the extra effort put towards detect­ing super­flu­ous DNA.

Gene Edit­ing ver­sus GMOs

What these recent find­ings also high­light is a more gen­er­al, but lit­tle-dis­cussed, aspect of gene edit­ing. Although the goals of gene-edi­tors and genet­ic engi­neers are assumed to be very dif­fer­ent, their stan­dard meth­ods are, in prac­tice, vir­tu­al­ly indistinguishable.

Con­sid­er crop plants, the sub­ject of much of the cur­rent com­mer­cial inter­est in gene-edit­ing. To edit crops, DNA is intro­duced into plant cells using what are stan­dard genet­ic engi­neer­ing meth­ods. These meth­ods can all cre­ate muta­tions. That is, they dam­age DNA. Depend­ing on the specifics of the method used, the col­lec­tive result can be ten thou­sand muta­tions per genome. For gene edit­ing of crops this means that one on-tar­get tweak’ may be dwarfed by thou­sands of off-tar­get ones.

The oth­er nec­es­sary com­par­i­son with Genet­i­cal­ly Mod­i­fied Organ­isms (GMOs) is their track record of being found, long after com­mer­cial­iza­tion, to have unin­tend­ed for­eign DNA, or trans­genes, present in their genomes. Cornell’s virus-resis­tant papaya, released in Hawai’i, turned out to con­tain at least five (and pos­si­bly six) sep­a­rate frag­ments of for­eign DNA. Cor­nell had pre­vi­ous­ly told reg­u­la­tors its papaya con­tained only two trans­genes. Anoth­er exam­ple: Monsanto’s Roundup Ready Soy­bean, by then grown on 96% of U.S. soy­bean acres, was found by inde­pen­dent researchers to have sub­stan­tial­ly more for­eign DNA than Mon­san­to had claimed.

So, if one only lis­tened to the rhetoric con­trast­ing pre­cise” tweaks” of gene edit­ing with messy,” ran­dom” genet­ic engi­neer­ing one would hard­ly sus­pect that, when it comes to plants, and often to ani­mals as well, there is lit­tle dif­fer­ence between the real­i­ty of gene edit­ing and that of genet­ic engineering.

Are there solutions?

The cas­es men­tioned above demon­strate that the gene-edit­ing indus­try, and not just Recom­bi­net­ics, is not show­ing much inter­est in self-exam­i­na­tion. Far greater even than the GMO indus­try before it, there is a cow­boy zeit­geist: Blow off prob­lems and rush to mar­ket. Thus most gene-edit­ing com­pa­nies are reluc­tant to share infor­ma­tion and con­se­quent­ly very lit­tle is known about how, in prac­tice, many of these com­pa­nies derive their gene-edit­ed’ products.

Many coun­tries are at present for­mu­lat­ing reg­u­la­tions for gene edit­ing. These will go a long way to deter­min­ing who ben­e­fits and who los­es from any poten­tial ben­e­fits that gene edit­ing may have. In any event, these results pro­vide a com­pelling case for active gov­ern­ment oversight.

But it is not just reg­u­la­tors who need to step up, how­ev­er. Investors, insur­ers, jour­nal­ists, every­one, in fact, should be ask­ing far more ques­tions of the sci­en­tists and com­pa­nies active in gene edit­ing. Oth­er­wise, boon is like­ly to stray into bane.

Editor’s Note: This is a revised ver­sion of an arti­cle orig­i­nal­ly pub­lished by Inde­pen­dent Sci­ence News. To read the orig­i­nal ver­sion, which dives deep­er into the sci­ence of gene edit­ing and con­tains a bib­li­og­ra­phy of ref­er­ence mate­ri­als, click here.

Jonathan R. Lath­am, PhD, is co-founder and exec­u­tive direc­tor of the Bio­science Resource Project, which is the pub­lish­er of Inde­pen­dent Sci­ence News (inde​pen​dentscience​news​.org). He has pub­lished sci­en­tif­ic papers in dis­ci­plines as diverse as plant ecol­o­gy, virol­o­gy, genet­ics, and RNA biology.
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