Add one fa­tal flaw to Jiankui He's litany of mis­takes in CRISPR ba­by de­ba­cle

Sci­en­tists the world over have found plen­ty of rea­sons to con­demn their Chi­nese col­league Jiankui He’s ex­per­i­ment with the world’s first CRISPR ba­bies late 2018: The al­leged med­ical need to con­fer HIV im­mu­ni­ty was un­found­ed, the con­sent process seemed du­bi­ous, the ac­tu­al gene edit­ing ap­peared spot­ty, just to name a few. But a new re­search pa­per may have un­cov­ered the most stag­ger­ing of them all.

Two re­searchers at UC Berke­ley has found that the ge­net­ic mu­ta­tion He at­tempt­ed to mim­ic in twins Lu­lu and Nana — known as CCR5-∆32 — is as­so­ci­at­ed with a high­er risk of pre­ma­ture death.

It’s been wide­ly re­port­ed that the mu­ta­tion, which in ef­fect knocked out the CCR5 gene, had al­ready been shown to ren­der peo­ple more sus­cep­ti­ble to the West Nile virus and more like­ly to suf­fer se­ri­ous com­pli­ca­tions, in­clud­ing death, from in­fluen­za. But the over­all ef­fect on mor­tal­i­ty has yet to be es­tab­lished.

By comb­ing through geno­type and death reg­is­ter de­tails of 410,000 in­di­vid­u­als UK Biobank, Berke­ley pro­fes­sor Ras­mus Nielsen and his post­doc Xinzhu Wei found a 21% in­crease in all-cause mor­tal­i­ty rate among peo­ple with two copies of the ∆32 mu­ta­tion, in which 32 base pairs are omit­ted from the gene.

Wei and Nielsen are quick to warn against over­in­ter­pret­ing their find­ings, not least be­cause they on­ly an­a­lyzed genomes of UK vol­un­teers, and they don’t nec­es­sar­i­ly trans­late to East Asians as “the ef­fect of the mu­ta­tion de­pends on the ge­net­ic back­ground and the en­vi­ron­ments,” Wei wrote to Na­tion­al Ge­o­graph­ic.

That said, a sim­i­lar point was al­so made with re­gards to the stud­ies that He cit­ed to jus­ti­fy in­tro­duc­ing the mu­ta­tion in the ba­bies in the first place. Signs that CCR5-∆32 had pro­tec­tive ef­fects against HIV, nat­u­ral­ly ob­served in Eu­ro­pean pop­u­la­tions, spurred him to en­gi­neer their trait in­to the em­bryos that even­tu­al­ly grew in­to twin ba­by girls.

No­tably, He didn’t ex­act­ly recre­ate the ∆32 mu­ta­tion in ei­ther em­bryo. Based on the slides he pre­sent­ed at a con­fer­ence in Hong Kong, Both in­fants ap­peared to still car­ry nor­mal copies of the CCR5 gene, and where the gene edit­ing did work it re­sult­ed in very dif­fer­ent mu­ta­tions whose ef­fects have nev­er been stud­ied.

Nonethe­less, these new find­ings once again lay bare the knowl­edge gap on the con­se­quences — good and bad — of gene vari­a­tions and, thus, the dan­gers of ap­ply­ing gene edit­ing tools on hu­man cells, es­pe­cial­ly when the al­ter­ations can be passed on­to fu­ture gen­er­a­tions as in the case of an em­bryo.

He him­self ex­pressed sec­ond thoughts about his ex­per­i­ment in an email ex­change with Stan­ford Uni­ver­si­ty bioethi­cist William Hurl­but, STAT’s Sharon Be­g­ley re­port­ed.

“I have been think­ing,” He wrote, “I rec­og­nize I pushed too quick­ly in­to a first-of-kind clin­i­cal study with­out the nec­es­sary open di­a­log with reg­u­la­tors, the sci­en­tif­ic com­mu­ni­ty, and the pub­lic.”

As gov­ern­ments and ex­perts rush to pro­pose new reg­u­la­tions on the bound­aries of gene edit­ing, with new stud­ies such as this, the world is fi­nal­ly hav­ing the con­ver­sa­tion that He — now com­plete­ly side­lined and close­ly mon­i­tored by Chi­nese au­thor­i­ties — didn’t have.


Im­age: Jiankui He in No­vem­ber 2018. KIN CHE­UNG for AP PHO­TO

Hal Barron, GSK

Break­ing the death spi­ral: Hal Bar­ron talks about trans­form­ing the mori­bund R&D cul­ture at GSK in a crit­i­cal year for the late-stage pipeline

Just ahead of GlaxoSmithKline’s Q2 update on Wednesday, science chief Hal Barron is making the rounds to talk up the pharma giant’s late-stage strategy as the top execs continue to woo back a deeply skeptical investor group while pushing through a whole new R&D culture.

And that’s not easy, Barron is quick to note. He told the Financial Times:

I think that culture, to some extent, is as hard, in fact even harder, than doing the science.

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UP­DAT­ED: Stay tuned: Bio­gen’s num­bers are great — it’s their wor­ri­some fu­ture that leaves an­a­lysts skit­tish

Biogen came out with an upbeat assessment of their Q2 numbers today, discounting the arrival of a key rival for its blockbuster Spinraza franchise. But the top execs remain grimly determined to not say much anything new about the sore points that have dragged down its stock, including the future of its big investment in Alzheimer’s or how it plans to invest the considerable cash that the big biotech continues to reap.

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Why wait? Cel­gene re­struc­tures a big Jounce pact — ze­ro­ing in on new I/O path­way with $530M deal and bump­ing ICOS

Celgene’s business team isn’t waiting for the big merger with Bristol-Myers Squibb to go through before syncing its strategy with the new mother ship.

Tuesday evening the big biotech unveiled a $530 million deal — $50 million in upfront cash — to amend their alliance with Jounce Therapeutics $JNCE to gain worldwide rights to JTX-8064, an antibody that targets the LILRB2 receptor on macrophages. Their old, $2.6 billion deal is being scrapped, leaving Jounce with a pipeline that includes the lead drug, the ICOS-targeting vopratelimab.

PACT Phar­ma says it's per­fect­ed the tech to se­lect neoanti­gens for per­son­al­ized ther­a­py — now on­to the clin­ic

At PACT Pharma, the lofty goal to unleash a “tsunami” of T cells personalized for each patient has hinged on the ability to correctly identify the neoantigens that form something of a fingerprint for each tumor, and extract the small group of T cells primed to attack the cancer. It still has a long way to go testing a treatment in humans, but the biotech says it has nailed that highly technical piece of the process.

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Vivek Ramaswamy’s Myovant $MYOV has closely matched its positive first round of Phase III data for their uterine fibroid drug relugolix, setting up a head-to-head rivalry with pharma giant AbbVie as the little biotech steers to the market with a planned filing in Q4.

Here’s how Myovant plans to prevail over the AbbVie $ABBV empire.

In the study, 71.2% of women receiving once-daily relugolix combination therapy achieved the clinical response they were looking for, compared to only 14.7% in the control arm. The data comfortably reflected the same outcomes in the first Phase III — 73.4% of women receiving once-daily oral relugolix combination therapy achieved the responder criteria compared with 18.9% of women receiving placebo — which will reassure regulators that they are getting the carefully randomized data that qualifies for the FDA’s gold standard for success.

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Some Big Phar­mas stepped up their game on da­ta trans­paren­cy — but which flunked the test?

The nonprofit Bioethics International has come out with their latest scorecard on data transparency among the big biopharmas in the industry — flagging a few standouts while spotlighting some laggards who are continuing to underperform.

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