CRISPR : can we reach a global consensus on genetic modification?

Since the birth of Lulu and Nana in 20218, two Chi­nese twins born from embryos in which a gene involved in HIV infec­tion was mod­i­fied, a red line has been crossed. Announced at the Sec­ond Inter­na­tion­al Sum­mit on Human Genome Edit­ing in Hong Kong, the event was described as “a fail­ure of self-reg­u­la­tion by the sci­en­tif­ic com­mu­ni­ty due to a lack of trans­paren­cy” by Nobel lau­re­ate David Bal­ti­more, who was co-chair­ing the ses­sion at the time.

The WHO imme­di­ate­ly inves­ti­gat­ed the issue. It man­dat­ed an Advi­so­ry Com­mit­tee of experts, of which I am a mem­ber, to pro­duce the first glob­al rec­om­men­da­tions on human genome mod­i­fi­ca­tion. After more than two years work, this com­mit­tee has just pre­sent­ed a set of good prac­tice rules to accom­pa­ny, from an eth­i­cal and legal point of view, the tech­no­log­i­cal rev­o­lu­tion rep­re­sent­ed by genome edit­ing, facil­i­tat­ed by the CRISPR-Cas9 sys­tem (Nobel Prize for Chem­istry 2020).

Since its devel­op­ment, this tech­nol­o­gy has been a source of hope for the treat­ment of rare dis­eases or can­cers. How­ev­er, even in the con­text of non-inher­i­ta­ble mod­i­fi­ca­tions, which are accept­ed by most cul­tures, the issues of med­ical rel­e­vance, equal­i­ty of access to treat­ment regard­less of the med­ical devel­op­ment of the patient’s coun­try, or the eco­nom­ic via­bil­i­ty of approach­es with strong intel­lec­tu­al prop­er­ty can­not be ignored.

From the out­set of our work, we have set out the main prin­ci­ples of appro­pri­ate gov­er­nance for the use of human genome mod­i­fi­ca­tion sys­tems. First and fore­most, it is impor­tant to include the con­text. Eco­nom­ic devel­op­ment, access to health care or the lev­el of sci­en­tif­ic exper­tise varies from one coun­try to the next. These fac­tors influ­ence the med­ical rel­e­vance or social accep­tance of med­ical approach­es. It is also essen­tial to estab­lish super­vi­sion of projects involv­ing the mod­i­fi­ca­tion of the human genome. The sci­en­tif­ic com­mu­ni­ty must be able to analyse the impli­ca­tions of each pro­gramme before­hand and mon­i­tor their imple­men­ta­tion fol­low­ing the work.

The UN agency also pro­pos­es to sup­port insti­tu­tions and gov­ern­ments in the devel­op­ment of their reg­u­la­tions on the use of human genome edit­ing tech­nolo­gies. Final­ly, this process must be done in dia­logue with the pub­lic. It is cru­cial to improve people’s under­stand­ing of the issues at stake in genome edit­ing, in order to pro­mote an inclu­sive and peace­ful debate. The WHO has cho­sen to pro­pose a gov­er­nance frame­work rather than hold­ing an inter­na­tion­al con­ven­tion. This approach is more flex­i­ble and can accom­mo­date the rapid evo­lu­tion of tech­nolo­gies and accom­pa­ny cur­rent human genome edit­ing pro­grammes for med­ical pur­pos­es while antic­i­pat­ing what will follow.

While the use of genome edit­ing tools to treat can­cer does not go against bioethics in prin­ci­ple, oth­er pur­pos­es are ques­tion­able. The most wor­ry­ing option involves her­i­ta­ble mod­i­fi­ca­tions, mean­ing those con­cern­ing either the gamete (sperm or egg) or the embryo. In such cas­es, the mod­i­fi­ca­tions would be trans­mit­ted to the patient’s descen­dants – and poten­tial­ly their respec­tive descen­dants. This prac­tice is pro­hib­it­ed in most coun­tries around the world. How­ev­er, there are legal grey areas where unscrupu­lous clin­ics may slip through the net. Although, giv­en the cur­rent state of the sci­ence, it is irre­spon­si­ble to mod­i­fy an individual’s genome in a her­i­ta­ble way: the mech­a­nisms for mod­i­fy­ing DNA are not the same in somat­ic cells (which ensure the func­tion­ing and struc­ture of the organ­ism) and in germ cells (which are like­ly to form gametes and whose genet­ic mate­r­i­al can be passed on to descen­dants). More­over, it is not known how these tools work out­side somat­ic cells and there are indi­ca­tions that they are not even reli­able in the germline.

To allow a her­i­ta­ble genome mod­i­fi­ca­tion it will have to meet three sets of cri­te­ria: sci­en­tif­ic, med­ical, and soci­etal. If one day a reli­able and con­trolled tech­nique with a near-zero risk of error were to be devel­oped, the sci­en­tif­ic con­text could be met and the deci­sion to use it to induce a her­i­ta­ble mod­i­fi­ca­tion could be con­sid­ered. For exam­ple, a seri­ous, incur­able, genet­i­cal­ly trans­mis­si­ble dis­ease for which pre-implan­ta­tion diag­no­sis (i.e. selec­tion of embryos not car­ry­ing the muta­tion), would not be pos­si­ble. This is like cas­es of risk to reces­sive genet­ic dis­eases where both mem­bers of a cou­ple are affect­ed and there­fore con­sti­tutes a med­ical con­text where her­i­ta­ble mod­i­fi­ca­tion could be dis­cussed. The sever­i­ty of the con­di­tion and the absence of oth­er pos­si­ble respons­es could lead to soci­etal approval, which is ulti­mate­ly necessary.

Does this open-end­ed think­ing encour­age a slip­pery slope to genome edit­ing for per­son­al con­ve­nience? No. Not if we main­tain the require­ment of triple rel­e­vance. For exam­ple, to reduce human impact on nat­ur­al resources, an eco-tran­shu­man­ist group pro­posed that humans should be only 80cm tall. As such, they envis­aged mod­i­fy­ing the genome of human off­spring to lim­it their height – but there is no med­ical rea­son what­so­ev­er for this inter­ven­tion to take place, so the pro­to­col was refused.

To car­ry out this reflec­tion, the WHO pro­pos­es to accom­pa­ny coun­tries in the devel­op­ment of respon­si­ble reg­u­la­tions. Nonethe­less, it is not a ques­tion of impos­ing a set of rules. Nations with dif­fer­ent legal approach­es, such as Ger­many and the Unit­ed King­dom, ensure a strict ban regime, although they are com­plete­ly dif­fer­ent. Sev­er­al avenues for respon­si­ble reg­u­la­tion are possible.

How­ev­er, the WHO will not be able to pre­vent a rogue state from cross­ing eth­i­cal bound­aries. The UN organ­i­sa­tion is a pow­er of influ­ence, not oblig­a­tion. Nev­er­the­less, since the start of this fact-find­ing mis­sion, Chi­na has passed new, more restric­tive laws, Rus­sia has for­mal­ly banned its researchers from her­i­ta­ble mod­i­fi­ca­tion of the human genome, and fer­til­i­ty clin­ics in Turkey have removed offers of germline mod­i­fi­ca­tion from their web­sites. All in all, a good start!

Interview by Agnès Vernet

• Human genome edit­ing: a frame­work for governance
• Human genome edit­ing: posi­tion paper