Experimental Gene Editing Treatment Reduces Dangerous Cholesterol in Study

"The trial involved only 10 patients, but it suggests cholesterol can be permanently reduced with a single treatment for patients at risk of heart disease.

The handful of patients had severe heart disease that had caused chest pain and heart attacks. After trying available cholesterol-lowering medications, they could not get their cholesterol as low as cardiologists recommended.

So they volunteered for an experimental cholesterol-lowering treatment using gene editing that was unlike anything tried in patients before.

The result, reported Sunday by the company Verve Therapeutics of Boston at a meeting of the American Heart Association, showed that the treatment appeared to reduce cholesterol levels markedly in patients and that it appeared to be safe.

The trial involved only 10 patients, with an average age of 54. Each had a genetic abnormality, familial hypercholesterolemia, that affects around one million people in the United States. But the findings could also point the way for millions of other patients around the world who are contending with heart disease, which remains a leading cause of death.

 In the United States alone, more than 800,000 people have heart attacks each year.

And while more trials in a broader range of patients will need to be carried out, gene editing experts and cardiologists said the treatment had the potential to transform preventive cardiology.

"Even for seasoned veterans of this field like myself, this is a day we will look back on," said Fyodor D. Urnov, a gene editor at the Innovative Genomics Institute in Berkeley, Calif. "I see today as crossing a Rubicon, in a good way. This is not a small step. It is a leap into new territory."

Impressed with the data and the potential it shows, the pharmaceutical giant Eli Lilly paid $60 million to to collaborate with Verve Therapeutics and opted to acquire additional rights to Verve's programs for an additional $250 million. If the editing continues to look promising, Eli Lilly expects to help with larger studies.

"Until now, we thought of gene editing as a treatment we should reserve for very rare diseases where there is no other treatment," said Dr. Daniel Skovronsky, Eli Lilly's chief scientific and medical officer. "But if we can make gene editing safe and widely available, why not go after a more common disease?"

The new study was led by Dr. Sekar Kathiresan, chief executive of Verve. 

Patients received a single infusion of microscopic lipid nanoparticles containing within them a molecular factory to edit a single gene in the liver, the site of cholesterol synthesis. The gene, PCSK9 [1], raises levels of LDL cholesterol, the bad kind. The plan was to block it.

The little lipid spheres were carried through the blood directly to the liver. They entered liver cells and opened up, revealing two molecules. One instructs DNA to make a gene editing tool, and the other is a guide to take the editing tool to the gene that needs editing.

The treatment "is almost like science fiction," said Dr. Martha Gulati, director of preventive cardiology at the Smidt Heart Institute of Cedars-Sinai Medical Center in Los Angeles and president of the American Society for Preventive Cardiology, who was not involved in the trial.

The gene editing tool acts like a pencil and an eraser. The eraser wipes out one letter of the target gene, and the pencil writes in a new one, turning off PCSK9.

The goal: a single cholesterol-lowering treatment that results in lifelong protection from heart disease.

Patients received varying doses. LDL levels in the three who received the highest doses fell by 39 to 55 percent -- enough to get them toward their cholesterol goal.

In the small study, those who received the higher doses had flulike symptoms for a few hours. Two patients had serious adverse events that the study's independent data safety and monitoring board deemed a result of their underlying severe heart disease. The board advised the researchers not to stop the study.

One had a fatal cardiac arrest five weeks after receiving the infusion. An autopsy showed that several of his coronary arteries were blocked.

The other patient had a heart attack the day after the infusion. It turned out that he had been having chest pain before receiving the infusion but had not reported it. If the investigators had known, he would not have received the treatment.

In a way, the treatment is a culmination of studies that began a decade ago when researchers discovered rare but healthy individuals with cholesterol levels that seemed impossibly low. The reason was that their PCSK9 gene was mutated and no longer functioned. As a result, these people were protected from heart disease.

That led to the development of antibodies to block the gene. Patients inject themselves with the antibodies once a week. Then came a twice-yearly RNA injection that prevents PCSK9 from being made.

It seemed possible that those treatments, as well as statins for those whose cholesterol is more easily controlled, could help solve the heart disease problem.

But heart disease persists as a killer. Even after people are diagnosed with heart disease, less than 60 percent of all patients take a statin. Only a quarter take one of the more effective, high-intensity statins, Dr. Gulati said.

"Patients take it initially, and then they forget or decide they don't need it," she explained. "That happens more than you'd think."

Dr. Michelle O'Donoghue, a cardiologist at Brigham and Women's Hospital, said that because patients so often do not take their pills or injections, "there is a lot of interest, through gene editing, of a one and done -- a single treatment and a lifetime response."

Family history was the inspiration for Dr. Kathiresan at Verve Therapeutics. His uncle and grandmother died of heart attacks. His father had a heart attack at age 54. And then, on Sept. 12, 2012, his 42-year-old brother, Senthil, returned from a run dizzy and sweaty. He was having a heart attack. He died nine days later.

At that moment, Dr. Kathiresan said, he vowed to find a way to prevent what had happened to his brother from happening to anyone else.

Of course, even if gene editing works, applying it to young people with heart risk is well into the future. But, Dr. Gulati said, early gene editing of younger patients with genetically high cholesterol levels might prevent arteries from hardening.

"It could be an incredible medicine," she said.

All this depends on success and safety of the gene editing and on its effects lasting. The first patient was treated just six months ago. But a previous study in monkeys lasted two and a half years, and the results of the gene editing persisted.

Dr. Urnov, who said he has a genetic risk for heart disease, is optimistic for himself and his 6-year-old daughter.

"I honestly cannot wait for this medicine to become available for heart disease prevention," he said. "I love the idea of having gene editing as a vaccine for the prevention of heart disease."" [2]

1. PCSK9 is proprotein convertase subtilisin/kexin type 9"


"PCSK9 is ubiquitously expressed in many tissues and cell types. PCSK9 binds to and degrades the receptor for low-density lipoprotein particles (LDL), which typically transport 3,000 to 6,000 fat molecules (including cholesterol) per particle, within extracellular fluid. The LDL receptor (LDLR), on liver and other cell membranes, binds and initiates ingestion of LDL-particles from extracellular fluid into cells and targets the complex to lysosomes for destruction. If PCSK9 is blocked, the LDL-LDLR complex separates during trafficking, with the LDL digested in the lysosome, but the LDLRs instead recycled back to the cell surface and so able to remove additional LDL-particles from the extracellular fluid. Therefore, blocking PCSK9 can lower blood LDL-particle concentrations."
   

 

2. Experimental Gene Editing Treatment Reduces Dangerous Cholesterol in Study: [National Desk]. Kolata, Gina.  New York Times, Late Edition (East Coast); New York, N.Y.. 13 Nov 2023: A.16.

Už viešųjų garantijų Kinijos vadovas Xi Jinpingas platino niūrią nuomonę apie JAV

„Kinijos lyderio kalbos rodo, kaip jis nuo pat valdymo pradžios ruošėsi stiprėjančiai konkurencijai su JAV.

 

Kai Kinijos prezidentas Xi Jinpingas 2015 m. surengė pirmąjį valstybinį vizitą Jungtinėse Valstijose, pagarbos reikalavimus jis apėmė patikinimais.

 

Jis draugavo su technologijų vadovais, gindamas Kinijos interneto kontrolę. Jis neigė, kad Kinija militarizavo ginčijamą Pietų Kinijos jūrą, tuo pat metu tvirtindama savo jūrines pretenzijas. 

 

Jis viltingai kalbėjo apie „naują didžiųjų galios santykių modelį“, kuriame Pekinas ir Vašingtonas taikiai sugyventų, kaip lygūs.

 

Tačiau grįžęs į Kiniją, susitikdamas su kariuomene, ponas Xi stulbinamai griežtai perspėjo, kad stiprėjanti konkurencija tarp kylančios Kinijos ir ilgai dominuojančių JAV yra neišvengiama ir kad Liaudies išlaisvinimo armija turėtų būti pasirengusi galimam konfliktui.

 

P. Xi pasakojime, Kinija siekė taikiai pakilti, tačiau Vakarų galios nesutiktų su mintimi, kad komunistų vadovaujama Kinija vejasi ir kada nors galėtų jas aplenkti pasauliniu lygmeniu. Vakarai niekada nenustos bandyti sužlugdyti Kinijos kilimą ir nuversti jos komunistų partiją, sakė jis savo kalbose kariuomenei, apie kurias žiniasklaida beveik nepraneša.

 

„Be jokios abejonės, didėjanti mūsų šalies stiprybė yra svarbiausias veiksnys, skatinantis iš esmės pertvarkyti tarptautinę tvarką“, – sakė jis aukščiausiems vadams 2015 m. lapkritį, praėjus dviem mėnesiams po vizito Jungtinėse Valstijose. „Kai kurios Vakarų šalys visiškai nenori, kad socialistinė Kinija sustiprėtų, vadovaujant Kinijos komunistų partijai.

 

Nepaisant jo patikinimo prezidentui B. Obamai nemilitarizuoti Pietų Kinijos jūros, 2016 m. vasario mėn. Xi pasakė savo vyresniesiems vadams, kad Kinija turi sustiprinti savo buvimą ten, sakydamas: „Pasinaudojome proga, pašalinome intervencijos šansus ir paspartinome statybas pietuose, Kinijos jūros salose ir seklumose, pasiekiant istorinį laivybos strategijos proveržį ir ginant jūrines teises. (Vėlesniais metais Kinija greitai išplėtė savo karinę infrastruktūrą šioje srityje.)

 

P. Xi pastabos yra tarp kalbų, kurias J. Xi pasakė Liaudies išlaisvinimo armijos ir komunistų partijos pareigūnams, rinkinių, kuriuos paskelbė kariuomenė, kad galėtų atlikti vyresniųjų karininkų vidinį apmokymą, ir kuriuos matė ir patvirtino „The New York Times“. Tomai „Xi Jinpingo pasirinkti pagrindiniai pareiškimai apie krašto apsaugą ir karinį vystymąsi“ apima jo pirmuosius valdymo metus nuo 2012 m. iki 2016 m. vasario mėn.

 

Šiose kalbose pateikiamas naujas, nedažytas vaizdas į lyderį, esantį XXI amžių formuojančios supervalstybės konkurencijos centre. Jie parodo, kaip kartais jis išsakydavo beveik fatališką įsitikinimą – net prieš tai, kai Pekino ryšiai su Vašingtonu vėliau smarkiai smuko Trumpo administracijoje – kad Kinijos iškilimas paskatins Vakarų konkurentų, siekiančių išlaikyti savo dominavimą, atsaką.

 

„Kuo greičiau vystysimės, tuo didesnis išorinis šokas bus ir tuo didesnis strateginis atotrankos smūgis“, – 2014 m. Kinijos oro pajėgų pareigūnams sakė ponas Xi.

 

P. Xi pasaulėžiūroje Vakarai siekė sugriauti Kinijos komunistų partijos galią namuose ir suvaldyti šalies įtaką užsienyje. Komunistų partija turėjo atsakyti į šias grėsmes geležine valdžia ir vis stipresne Liaudies išlaisvinimo armija.

 

Šią savaitę ponui Xi ruošiantis susitikti su prezidentu Bidenu Kalifornijoje, klausimas, kaip šios dvi jėgos suvaldys savo konkurenciją, kyla dėl santykių.

 

P. Xi bandė stabilizuoti santykius su Vašingtonu, matyt, slėgė Kinijos ekonominės bėdos ir noras sumažinti Pekino diplomatinę izoliaciją. „Mes turime tūkstančius priežasčių stiprinti santykius tarp Kinijos ir JAV, ir nė vienos juos sugriauti“, – neseniai Pekine amerikiečių įstatymų leidėjams sakė ponas Xi.

 

Tačiau abipusiam nepasitikėjimui gilėjant, bet koks abiejų pusių priešpriešos sumažinimas gali būti menkas.

 

Ponas Xi pabrėžė, kad jo sprendimas dėl Jungtinių Valstijų keliamo iššūkio išlieka nepakitęs, o kovo mėnesį retai viešai pasakė: „Vakarų šalys, vadovaujamos JAV, įgyvendino visapusišką Kinijos sutramdymą, apsupimą ir slopinimą“.

 

Abejonės dėl Amerikos galios

 

P. Xi požiūris į pasaulį ir JAV yra audringų Kinijos metų, kai jis ruošėsi perimti valdžią, pėdsakas. Kinija augo greitai, bet reformos, kurios paskatino augimą, sulėtėjo, o pareigūnų korupcija siautėjo. Saugumo valstybė išsiplėtė, bet taip pat ir protestai bei nesutarimai.

 

Kai 2007 m. Xi tapo laukiančiu šalies lyderiu, kai kurie diplomatai, ekspertai ir komunistų partijos veteranai prognozavo, kad jis būtų pragmatikas, galintis iš naujo pradėti Kinijos pastangas liberalizuoti ekonomiką. Kai kurie netgi įžvelgė jame politinių pokyčių galimybę po ilgo sąstingio laikotarpio.

 

Jie paminėjo Xi kilmę, kaip revoliucijos lyderio, padėjusio prižiūrėti Kinijos ekonomikos pertvarką devintajame dešimtmetyje, sūnaus ir dešimtmečius, kai p. Xi praleido, kaip pareigūnas Rytų Kinijos komercinėse pakrantės provincijose, įskaitant 17 metų Fudziane, kur jis  piršo investuotojams iš kaimyninio Taivano. Li Rui, išėjęs į pensiją aukšto rango pareigūnas, kadaise dirbęs Mao Zedongo padėjėju, 2007 metais savo dienoraštyje įrašė pokalbį apie gana nežinomą poną Xi.

 

„Paklausiau, koks yra Xi Jinpingas, o atsakymas buvo keturi žodžiai: „valdyti nieko nedarant“, – rašė ponas Li. „Būtų gerai, – pridūrė ponas Li, – leisti kiekvienam išnaudoti savo stipriąsias puses ir mažiau kištis. (Ponas Li mirė 2019 m.; jo dienoraščius ir susirašinėjimus saugo Stenfordo universiteto Hoover institutas.)

 

Tačiau pono Xi auklėjimas ir šeimos kilmė paliko sudėtingesnį pėdsaką, nei daugelis manė: jis visų pirma didžiavosi partija ir komunistine revoliucija. Skepticizmas Amerikos galios atžvilgiu ir atsargumas dėl jos ketinimų Kinijos atžvilgiu Pekine tapo populiaresnis, kai ponas Xi ruošėsi perimti valdžios vadeles.

 

2007–2008 m. pasaulinė finansų krizė sugriovė oficialias Kinijos prielaidas, kad Vašingtono ekonominės politikos formuotojai yra kompetentingi, net jei Pekinas su jomis nesutiko. Kinijos pareigūnai klausinėjo Amerikos pareigūnų, tokių, kaip Hankas Paulsonas, tuometinis iždo sekretorius, apie tai, kaip jie netinkamai elgėsi su situacija. Daugeliui Pekine pamokos apėmė ne tik finansų sistemą.

 

„Tai buvo lemiamas momentas“, – sakė Desmondas Shumas, verslininkas, kurio atsiminimuose „Raudonoji ruletė“ aprašomi tie metai, kai jis draugavo su Kinijos politiniu elitu. „Po to visas vakarietiškas modelis buvo daug labiau kvestionuojamas. Taip pat stiprėjo tikėjimas, kad pasauliui reikės Kinijos, kuri parodytų kelią iš netvarkos."

 

„Spalvotos revoliucijos“ šmėkla

 

Kai ponas Xi ruošėsi tapti Kinijos lyderiu, Rusijos prezidentas Vladimiras V. Putinas išryškėjo, kaip  stipruolio, besiveržiančio stoti prieš Amerikos pranašumą, pavyzdys.

 

„Šie du vyrai turi bendrą mentalinį pasaulio žemėlapį – ne visiškai vienodą, bet bendrą“, – sakė Strateginių ir tarptautinių studijų centro Kinijos ekspertas Jude'as Blanchette'as. „Abu nori grąžinti savo šalis į prarastą didybės paveldą; abu nori susigrąžinti pagrindines teritorijas; abu turi bendrą Sovietų Sąjungos žlugimo traumos jausmą."

 

Visų pirma, 2010 m. susitikę ponas Xi ir V. Putinas įtarė, kad JAV buvo linkusios destabilizuoti savo konkurentus, kurstydamos maištą vardan demokratijos. P. Xi ir kiti Kinijos lyderiai perėmė V. Putino „spalvotųjų revoliucijų“ sampratą, kad apibūdintų tokius neramumus.

 

2000-ųjų viduryje oficialūs Kinijos nuogąstavimai, kad prasidės protestai prieš partiją, neatrodė tokie naivūs. Akivaizdi korupcija ir oficialūs skandalai supykdė daugybę žmonių. Internetas atvėrė naujus kanalus skundams sustiprinti.

 

Kinijos komunistų partijos lyderiai ilgą laiką siekė sutelkti paramą, nurodydami išorinių grėsmių miazmą. Įspėjimai apie amerikiečių sąmokslą nuversti partiją ir „taikios evoliucijos“ būdu paversti Kiniją kapitalistine šalimi siekia Mao erą. Tačiau ponas Xi labai skubiai iškėlė šiuos įspėjimus.

 

„Jis yra žmogus, kuris savo gyvenimo metus praleido, stokojantis saugumo, ir, kaip jis sakė vėliau, iš savo tėvo mokęsis apie žmonių santykių ir galios nepastovumą“, – sakė Stenfordo universiteto Huverio istorijos laboratorijos mokslinis bendradarbis Josephas Torigianas. 

 

„Dabar jis tampa įvardytu įpėdiniu, dairosi po pasaulį ir mato „spalvotąsias revoliucijas“ bei JAV kišimąsi, o būtent jam atrodo, kad, galiausiai, valdžia yra paskutinis saugumo ir stiprybės garantas."

 

P. Xi matė pamokas „arabų pavasario“ sukilimuose, kurie nuvertė korumpuotus autoritarinius lyderius Vidurio Rytuose. Egipto lyderio Hosnio Mubarako nuvertimas 2011 m. paliko gilų įspūdį Kinijos lyderiams, kurie matė paraleles su 1989 m. demokratijos šalininkų protestais Tiananmenio aikštėje Pekine, sakė buvęs Centrinės žvalgybos valdybos pareigūnas Johnas K. Culveris, sekęs paskui p. Xi iškilimą.

 

  „Tai, kas juos iš tikrųjų išgąsdino, buvo Egiptas, nes Hosni Mubarakas iškilo kaip Egipto kariuomenės karininkas, tačiau kariuomenė atsigręžė prieš jį“, – sakė J. Culveris. Jis pridūrė, kad Kinijos lyderiai „tai pamatė ir paklausė savęs: „Jei šiandien įvyktų Tiananmenio aikštė, ar kariuomenė vėl išgelbėtų partiją?"

 

Xi karinė renovacija

 

Per kelias savaites nuo valdžios perėmimo 2012 m. pabaigoje P. Xi susitiko su pareigūnais ir ten skambėjo įspėjimas: Sovietų Sąjungos žlugimas, anot jo, Kinijai buvo įspėjamasis pasakojimas. Jis apgailestavo, kad ji žlugo, nes Sovietų Sąjungos kariškiai prarado nervus. Jis perspėjo pareigūnus, kad Kinijos gali ištikti toks pat likimas, jei partija neatgaus ideologinio stuburo.

 

Po kelių mėnesių jis išleido vidinį įsaką, siekdamas panaikinti jo vadinamų Vakarų idėjų, tokių, kaip visuotinių žmogaus teisių ir teisinės valstybės koncepcija, įtaką universitetuose ir žiniasklaidoje.

 

Anot Beno Rhodeso, buvusio B. Obamos patarėjo nacionalinio saugumo klausimais pavaduotojo nuo pirmojo prezidento viršūnių susitikimo su B. Obama 2013 m. Xi parodė, kad yra „daug ryžtingesnis ir labiau pasitikintis lyderis“, nei jo pirmtakas Hu Jintao, .

 

„Tai buvo vaikinas, kuris buvo ne tik partijos veidas, bet ir savo paties žmogus“, – elektroniniame laiške sakė ponas Rhodesas.

 

P. Xi, vadovaujantis kariuomenei, kaip Centrinės karinės komisijos pirmininkas, kai kuriuos savo niūriausius įspėjimus apie Vakarus skyrė jos vadams.

 

„Tarptautinės konkurencijos „džiunglių dėsniai“ nepasikeitė“, – 2014 m. jis sakė Kinijos nacionalinės įstatymų leidžiamosios valdžios kariniams delegatams. Jis atkreipė dėmesį į didėjantį Amerikos reaktyvinių lėktuvų, laivų ir lėktuvnešių buvimą Azijos ir Ramiojo vandenyno regione, kaip įrodymą, kad JAV siekė suvaldyti Kiniją.

 

Jis taip pat pareiškė, kad provakarietiški protestai, kurie tuomet apėmė visą Ukrainą, buvo įspėjimas Pekinui. „Kai kurios Vakarų šalys ten kursto ugnį ir slapta siekia ten pasiekti savo geopolitinius tikslus“, – sakė jis. „Turime atsižvelgti į šią pamoką“.

 

Pasak jo, kad pasirengtų J. Xi laukiančioms grėsmėms, Kinija turėjo skubiai pertvarkyti savo kariuomenę. Nuo 2015 m. pabaigos jis inicijavo didžiulį Liaudies išlaisvinimo armijos reorganizavimą, siekdamas, kad ji taptų integruota pajėga, galinčia išplėsti Kinijos galią užsienyje, ypač per oro, jūrų ir kosmoso pajėgas. Jo perspėjimai apie Vakarus padėjo pabrėžti tų pokyčių skubumą.

 

„Kalbos žmonėms sistemos viduje yra bandymas mobilizuotis“, – sakė Vašingtone dirbantis mokslininkas ponas Blanchette. „To nepadarysi tik sakydamas, kad pasaulis šiek tiek komplikuojasi; jums reikia pasakojimo, kuris leistų jums sugriauti įsitvirtinusius interesus, kad pasiektumėte pokyčių."

 

Ponas Xi perspėjo, kad Liaudies išlaisvinimo armija vis dar pavojingai atsilieka ir gali atsilikti, jei nesieks naujovių, ypač tobulindama savo ginkluotę ir vadovavimo organizaciją. Šiose kalbose p. Xi nesakė, kad karas neišvengiamas. Tačiau jis aiškiai pasakė, kad be didžiulės kariuomenės Kinija negalės pareikšti savo valios.

 

„Tarptautinėse varžybose politinės operacijos yra labai svarbios, bet galiausiai tai priklauso nuo to, ar tu turi jėgų ir ar gali tą jėgą panaudoti“, – 2015 m. lapkritį jis sakė Centrinės karinės komisijos vadams. "Vien tik sidabrinis liežuvis neveikia."

 

Amy Chang Chien prisidėjo prie reportažų Taipėjuje.

 

Chrisas Buckley, vyriausiasis „The Times“ korespondentas Kinijoje, taip pat praneša apie Kiniją ir Taivaną, daugiausia dėmesio skirdamas politikai, socialiniams pokyčiams ir saugumo bei kariniams klausimams."

 

Behind Public Assurances, Xi Jinping Has Spread Grim Views on U.S.

"Speeches by the Chinese leader show how he was bracing for an intensifying rivalry with the United States from early in his rule.

When President Xi Jinping of China made his first state visit to the United States in 2015, he wrapped his demands for respect in reassurances.

He courted tech executives, while defending China’s internet controls. He denied that China was militarizing the disputed South China Sea, while asserting its maritime claims there. He spoke hopefully of a “new model” for great power relations, in which Beijing and Washington would coexist peacefully as equals.

But back in China, in meetings with the military, Mr. Xi was warning in strikingly stark terms that intensifying competition between a rising China and a long-dominant United States was all but unavoidable, and that the People’s Liberation Army should be prepared for a potential conflict.

In Mr. Xi’s telling, China sought to rise peacefully, but Western powers would not accept the idea that a Communist-led China was catching up and could someday overtake them in global primacy. The West would never stop trying to derail China’s ascent and topple its Communist Party, he said in speeches to the military that are largely unreported by the media.

“Beyond doubt, our country’s growing strength is the most important factor driving a profound readjustment of the international order,” he told top commanders in November 2015, two months after his visit to the United States. “Some Western countries absolutely never want to see a socialist China grow strong under the leadership of the Chinese Communist Party.”

Despite his assurances to President Obama not to militarize the South China Sea, Mr. Xi told his senior commanders in February 2016 that China must bolster its presence there, saying: “We’ve seized the opportunity, eliminated intervention and sped up construction on South China Sea islands and shoals, achieving a historic breakthrough in maritime strategy and defending maritime rights.” (In the years that followed, China quickly expanded its military infrastructure in the area.)

Mr. Xi’s remarks are among collections of speeches that Mr. Xi made to the People’s Liberation Army and Communist Party officials, published by the military for internal study by senior officers, and seen and corroborated by The New York Times. The volumes, “Xi Jinping’s Selected Major Statements on National Defense and Military Development,” cover his initial years in power, from 2012 to February 2016.

The speeches offer a new, unvarnished view into the leader at the center of a superpower rivalry that is shaping the 21st century. They show how at times he has voiced an almost fatalistic conviction — even before Beijing’s ties with Washington took a steep dive later in the Trump administration — that China’s rise would prompt a backlash from Western rivals seeking to maintain their dominance.

“The faster we develop, the bigger the external shock will be, and the greater the strategic blowback,” Mr. Xi told Chinese Air Force officers in 2014.

In Mr. Xi’s worldview, the West has sought to subvert the Chinese Communist Party’s power at home and contain the country’s influence abroad. The Communist Party had to respond to these threats with iron-fisted rule and an ever-stronger People’s Liberation Army.

As Mr. Xi prepares to meet with President Biden in California this week, the question of how the two powers will manage their rivalry hangs over the relationship.

Mr. Xi has been trying to stabilize relations with Washington, apparently pressed by China’s economic troubles and a desire to reduce Beijing’s diplomatic isolation. “We have a thousand reasons to grow the relationship between China and the United States, and none at all to ruin it,” Mr. Xi told American lawmakers in Beijing recently.

But with mutual distrust running deep, any easing of antagonism between the two sides could be tenuous.

Mr. Xi underscored that his judgment of the challenge posed by the United States remains unchanged, saying with rare public bluntness in March: “Western countries led by the United States have implemented all-around containment, encirclement and suppression of China.”

Doubts About American Might

Mr. Xi’s views of the world and the United States bear the imprint of China’s turbulent years when he was preparing to assume power. China had grown quickly, but the reforms that boosted that growth had slowed, and official corruption was rampant. The security state had expanded, but so had protest and dissent.

As Mr. Xi emerged as the country’s leader-in-waiting in 2007, some diplomats, experts and well-connected Communist Party veterans predicted that he would be a pragmatist who might restart China’s efforts toward economic liberalization. Some even saw in him a chance for political change after a long period of stagnation.

They cited Mr. Xi’s pedigree as the son of a revolutionary leader who had helped oversee China’s economic overhaul in the 1980s and the decades Mr. Xi had spent as an official in the commercial coastal provinces of eastern China, including 17 years in Fujian, where he courted investors from neighboring Taiwan. Li Rui, a retired senior official who had once served as Mao Zedong’s aide, recorded in his diary a conversation in 2007 about the relatively unknown Mr. Xi.

“I asked what Xi Jinping was like, and the answer was four words: ‘governing by doing nothing,’” Mr. Li wrote. “That would be good,” Mr. Li added, “letting everyone play to their strengths with less meddling.” (Mr. Li died in 2019; his diaries and correspondences are held by the Hoover Institution at Stanford University.)

But Mr. Xi’s upbringing and family background left a more complex imprint than many assumed: He was, above all, proud of the party and the Communist revolution. And skepticism about American might and wariness about its intentions toward China were becoming more mainstream in Beijing as Mr. Xi prepared to take the reins of power.

The global financial crisis of 2007-08 had shattered official Chinese assumptions that Washington’s economic policymakers were competent, even if Beijing disagreed with them. Chinese officials quizzed American officials like Hank Paulson, then the Treasury secretary, about their mishandling of the situation. For many in Beijing, the lessons extended beyond the financial system.

“It was a defining moment,” said Desmond Shum, a businessman whose memoir, Red Roulette, describes those years, when he mingled with China’s political elite. “After that point, the entire Western model was questioned much more. There was also this growing belief that the world would need China to lead the way out of the mess.”

Specter of ‘Color Revolution’

As Mr. Xi prepared to become China’s leader, President Vladimir V. Putin of Russia was emerging as a model of an authoritarian strongman pushing back against American pre-eminence.

“These two men have a shared mental map of the world — not perfectly the same, but shared,” said Jude Blanchette, a China expert at the Center for Strategic and International Studies. “Both want to return their countries to a lost inheritance of greatness; both want to reclaim key territories; both have a shared sense of the trauma of the collapse of the Soviet Union.”

In particular, Mr. Xi and Mr. Putin, who met in 2010, shared a suspicion that the United States was bent on destabilizing its rivals by instigating insurrection in the name of democracy. Mr. Xi and other Chinese leaders adopted Mr. Putin’s conception of “color revolutions” to describe such unrest.

In the mid-2000s, official Chinese fears of an eruption of anti-party protests did not seem so far-fetched. Flagrant corruption and official scandals had incensed many people. The internet opened up new channels for amplifying grievances.

Chinese Communist Party leaders have long sought to mobilize support by citing a miasma of external threats. Warnings of an American conspiracy to overthrow the party and transform China into a capitalist country by “peaceful evolution” go back to the Mao era. But Mr. Xi has evoked those warnings with distinct urgency.

“He’s somebody who spent years of his life lacking security and, as he said later, learning from his father about the fickleness of human relationships and power,” said Joseph Torigian, a research fellow at the Hoover History Lab at Stanford University who has examined Mr. Xi’s speeches to the military. “Now he becomes the named successor, and he’s looking around the world and seeing ‘color revolutions’ and United States meddling and, for him, it’s this idea that, ultimately, power is the last guarantor of security and strength.”

Mr. Xi saw lessons in the “Arab Spring” uprisings that had toppled corrupt authoritarian leaders across the Middle East. The overthrow of Egypt’s leader, Hosni Mubarak, in 2011, left a deep impression on Chinese leaders, who saw parallels with the 1989 pro-democracy protests at Tiananmen Square in Beijing, said John K. Culver, a former Central Intelligence Agency officer who followed Mr. Xi’s rise.

 “What really scared them was Egypt, because Hosni Mubarak rose as an officer in the Egyptian military, and yet the military turned on him,” Mr. Culver said. Chinese leaders, he added, “saw that and asked themselves: ‘If Tiananmen Square happened today, would the army again save the party?’”

Xi’s Military Renovation

Within weeks of taking power in late 2012, Mr. Xi met with officials and sounded a warning: The collapse of the Soviet Union, he said, was a cautionary tale for China. It had fallen, he lamented, because its military had lost its nerve. He warned officials that China could suffer the same fate unless the party recovered its ideological backbone.

Months later, he issued an internal edict to roll back the influence of what he called Western ideas, such as the concept of universal human rights and the rule of law, in universities and the news media.

From his first presidential summit with Mr. Obama in 2013, Mr. Xi had shown himself to be a “much more assertive and confident leader” than his predecessor, Hu Jintao, setting aside his talking points to press his views, according to Ben Rhodes, a former deputy national security adviser to Mr. Obama.

“This was a guy who was not just the frontman of a party, he was his own man,” Mr. Rhodes said in an email.

Mr. Xi, who leads the military as chairman of the Central Military Commission, reserved some of his bluntest warnings about the West for his commanders.

“The ‘laws of the jungle’ of international competition have not changed,” he told military delegates to China’s national legislature in 2014. He pointed to the growing presence of American jets, ships and aircraft carriers in the Asia-Pacific region as evidence that the United States was seeking to contain China.

He also said that the pro-Western protests that were then sweeping across Ukraine were a warning for Beijing. “Some Western countries are fanning the flames there and secretly scheming to achieve their geopolitical goals there,” he said. “We must take heed of this lesson.”

To prepare for the threats Mr. Xi saw ahead, he said, China needed to urgently overhaul its military. From late 2015, he initiated a sweeping reorganization of the People’s Liberation Army, seeking to make it an integrated force capable of extending Chinese power abroad, especially through air, sea and space forces. His warnings about the West helped underscore the urgency of those changes.

“Speeches to people within the system are attempts to mobilize,” said Mr. Blanchette, the researcher in Washington. “You don’t do that by just saying that the world is getting a little bit complicated; you need a narrative that is going to allow you to smash vested interests to achieve change.”

Mr. Xi warned that the People’s Liberation Army was still dangerously backward, and could fall behind if it did not seek to innovate, particularly in upgrading its weaponry and command organization. In these speeches, Mr. Xi did not say that war was unavoidable. But he made clear that without a formidable military, China would not be able to assert its will.

“In international contestation, political operations are very important, but ultimately it comes down to whether you have strength and whether you can use that strength,” he told the commanders on the Central Military Commission in November 2015. “Relying on a silver tongue won’t work.”

Amy Chang Chien contributed reporting in Taipei.

Chris Buckley, the chief China correspondent for The Times, reports on China and Taiwan from Taipei, focused on politics, social change and security and military issues. More about Chris Buckley"