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

Herve Chneiweiss
Hervé Chneiweiss
CNRS Research Director, Neurobiologist and Chair of Inserm Ethics Committee

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.

CRISPR, the technology that makes (almost) anything possible

CRISPR is a mol­e­c­u­lar scis­sor that can mod­i­fy DNA with unprece­dent­ed pre­ci­sion, to the order of a sin­gle nucleotide (the basic unit of DNA: A, T, C or G). Emmanuelle Char­p­en­tier and Jen­nifer Doud­na, who dis­cov­ered it, were award­ed the Nobel Prize in Chem­istry in 2020 – only 8 years after their dis­cov­ery. This rapid award is due to the ease and reli­a­bil­i­ty of using CRISPR.

It is a sys­tem that con­sists of an enzyme – Cas9 – and a short strand of RNA, the guide sequence, which pre­cise­ly tar­gets the place in the genome to be cut. The cel­l’s nat­ur­al repair mech­a­nisms then cor­rect the DNA, break, and com­plete the mod­i­fi­ca­tion. CRISPR is now the ref­er­ence tool for mol­e­c­u­lar biol­o­gy and gene therapy.

On mus­cle, skin or even brain cells, the use of CRISPR must meet the eth­i­cal stan­dards of human genome mod­i­fi­ca­tion (med­ical rel­e­vance, respect for bio­log­i­cal mate­r­i­al of donors, con­sent, safe­ty, etc.). If the mod­i­fi­ca­tion tar­gets embry­on­ic cells or gametes (oocytes or sper­ma­to­zoa), it can be trans­mit­ted to descen­dants. This pos­si­ble inher­i­tance rais­es addi­tion­al questions.

Gene modification: what relevance?

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.

The risks inherited modifications

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.

WHO: the rules of good practice

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

Further reading


Herve Chneiweiss

Hervé Chneiweiss

CNRS Research Director, Neurobiologist and Chair of Inserm Ethics Committee

Hervé Chneiweiss has chaired the Inserm Ethics Committee since 2013. He is a member of the World Health Organization (WHO) Expert Advisory Committee on the development of global standards for the governance and oversight of human genome editing.