title: CKY (band)

text: In promotion of "Volume 1", CKY joined the 1999 Warped Tour, although after taking part in a protest started by fans regarding vending prices they were removed from the tour. Later in the year, the band signed a record deal with Volcom Entertainment, who reissued "Volume 1" twice in early 2000 – firstly under the title "CKY", crediting the group as Camp, and secondly under the title "Camp", crediting the group as CKY. In February, the group fired Bruni as they were "disappointed by his abilities and performance" on the Warped Tour, and he was replaced by Vernon Zaborowski in July, after Ginsburg briefly filled in on bass. The band returned to the Warped Tour in 2000, and the limited edition EP "Disengage the Simulator" was released later in the year. CKY's music began appearing on "Jackass" in October 2000, which is said to have generated "a flood of new fans".


title: CKY (band)

text: In May 2001, CKY ended their partnership with Volcom and signed with The Island Def Jam Music Group. After more remastered reissues of "Volume 1", the band recorded its second studio album "Infiltrate•Destroy•Rebuild" between November 2001 and January 2002, and released it in September 2002. The album gave the band its first experience of chart success, when it reached number 99 on the US "Billboard" 200. The single "Flesh into Gear" also charted, reaching number 39 on the "Billboard" Mainstream Rock chart.


title: CKY (band)

text: The group began touring the United States in promotion of the album, but in November was invited by Guns N' Roses frontman Axl Rose to perform in Vancouver as the opening warm-up act for the Chinese Democracy Tour, just three days before it was due to begin. Speaking about the news, Margera revealed that CKY had to cancel two of their own shows in California in order to travel to the Guns N' Roses concert, but admitted that he was "psyched because that's probably the biggest tour of [the] year". However, due to a delayed flight blamed on "mechanical troubles", Rose failed to arrive to Vancouver in time and the show had to be cancelled, inciting riots started by audience members. It was later announced that CKY would return to perform on the remainder of the United States leg of the tour, which was scheduled to run until January 2003. It was ultimately cancelled almost a month early.


title: CKY (band)

text: CKY toured throughout the rest of 2003 on the Out on the Noose Again Tour, which was delayed when Ginsburg broke his tailbone after falling down a flight of stairs. The band secured a high-profile support slot for Metallica in May 2003, after frontman James Hetfield personally approached Miller with the opportunity. The band's first video album, "", was released in November 2003, featuring music videos for all ten tracks from the 2002 album as well as "96 Quite Bitter Beings" and "Disengage the Simulator", behind-the-scenes features, and a three-hour documentary titled "CKY: Chopped & Sliced". Two-track EP "Hellview" was also released in 2003.


title: CKY (band)

text: On April 7, 2004, the band returned to the studio to begin recording the follow-up to "Infiltrate•Destroy•Rebuild". Band members periodically offered updates on the album, with Miller labelling it a "masterpiece" and "the best rock record of 2005", and Ginsburg calling it "an instant classic". Zaborowski was fired from the band in June 2004, with Ginsburg once again filling in on bass for a number of live shows. "Familiar Realm" was released as the lead single from the new album in May 2005, reaching number 32 on the Mainstream Rock chart. "An Answer Can Be Found" followed in June, reaching number 35 on the "Billboard" 200. According to Nielsen SoundScan, the album sold 27,786 copies in the United States in its first week of release.


title: CKY (band)

text: It was announced in July 2005 that former All That Remains bassist Matt Deis had replaced Zaborowski, performing his first show with the band on July 18 at the Whisky a Go Go in West Hollywood, California. The new lineup set out on tour to promote "An Answer Can Be Found", joining the Rock Adio Tour arranged by skateboarding company Adio Footwear with Fireball Ministry and The Knives, which ran between August and September. Later tour dates included a headline performance at Skate Fest in Worcester, Massachusetts, a UK stint with Clutch between September and October, and a North American tour with Avenged Sevenfold in early 2006.


title: CKY (band)

text: The band ended its partnership with Island in April 2006. Speaking at the time, Miller explained that the band had been asking to leave the label since 2003, claiming it "had no idea how to market a band that doesn't write songs about breaking up with their girlfriends".


title: CKY (band)

text: In December 2006, it was announced that CKY had signed a global recording contract with Roadrunner Records, a label which both Miller and Margera praised. Recording for the band's fourth studio album began at Ginsburg's Studio CIG Pennsylvania in January 2007. In March it was reported that the band had almost finished recording the album, with the song titles "Hellions on Parade" and "The Boardwalk Body" being confirmed. Speaking about the production process, Margera commented that the band was approaching it differently than it did for "An Answer Can Be Found", which he described as "a total guitar record". The band released another update in August, naming a number of new tracks and claiming that the album would be "easily out" by March or April 2008.


title: CKY (band)

text: However, in October 2007 it was reported that there were internal tensions within the band. MTV reported that "there's trouble in the world of CKY", explaining that an altercation had broken out between Miller and Ginsburg following an incident after a gig in St. Louis, Missouri. Each of the two had different recollections of the situations – Ginsburg proposed that Miller had "quit CKY to pursue his own band", and that he and Margera would continue CKY without him; Miller retorted by claiming that he had, according to MTV, "overheard several of his bandmates talking smack about him in St. Louis", after which he took a brief break from the group in the hope that he would receive an apology from his bandmates. After around a year with no updates, it was reported in October 2008 that the band was almost finished with the upcoming album. Recording was completed by November.


title: CKY (band)

text: "Carver City" was officially announced in January. Miller described the album as "the most collaborative and focused CKY effort to date", while Ginsburg applauded it as "more inventive and more layered than our past releases ... the most inspired album we have ever made". "Hellions on Parade" was released as the first single from the album in April, followed by "A#1 Roller Rager" on May 4. "Carver City" was released later in the month, charting at number 46 on the "Billboard" 200 and selling 11,000 copies in the US in its first week.


title: CKY (band)

text: CKY began touring in promotion of "Carver City" in June 2009, performing dates in North America with support acts ASG and Graveyard until August, when the run ended with a "hometown show" in Philadelphia. Later in the year the band visited several countries in Europe, and in January 2010 played in Japan for the first time. Later tour dates in 2010 included performances at Sonisphere Festival in the UK on August 1, which Miller described as "he biggest highlight of CKY's summer touring schedule by far", and shows in Australia and New Zealand.


title: CKY (band)

text: In May 2010, it was announced on CKY's official website that Deis "could no longer commit" to the band. He was later replaced by Matt "Matty J" Janaitis. In September the band released the single "Afterworld", which was the first song by the band to feature vocals by Ginsburg. The song was written for the third "Jackass" film, "Jackass 3D", and was included in its closing credits upon release in October. It was later revealed that the song would also be featured on an upcoming compilation album titled "B-Sides & Rarities", which featured a number of previously unreleased and out-of-print tracks and was released in March 2011. In promotion of the album, CKY completed a US tour in March. "B-Sides & Rarities" was later released on vinyl featuring a number of additional tracks in September 2011.


title: CKY (band)

text: The future of the band was once again cast into doubt in July 2011, when members disagreed about its future. In a video titled "CKY – What Next?", Miller noted that he and Margera had the idea for each of the band's members to record individual albums and then release them as an overall "CKY" package, which Janaitis also supported. However, Ginsburg was opposed to the plan, claiming that he would prefer to record a follow-up to "Carver City". Miller presented an alternate version of events in an interview in October 2015, claiming that it was Ginsburg's idea initially to produce albums in other bands (Miller in World Under Blood, Ginsburg in Rudy & Blitz and Margera in The Company Band), before a disagreement between the guitarist and his former bandmates left him without a side project. The rift escalated in the days and weeks following the release of the video, as Miller claimed on his Facebook page that Ginsburg had left the band, before himself announcing that he too would be "throwing the towel in" after completing the group's upcoming shows. Margera cited Miller's alcohol abuse as one of the causes of the tensions. The band performed a show dubbed "Christmas with CKY" on December 18 in Reading, Pennsylvania, which Ginsburg labelled on Twitter as the last CKY show.


title: CKY (band)

text: CKY returned in February 2012 with Year Long Disaster vocalist and guitarist Daniel Davies in place of founding frontman Miller, performing at the Australian festival Soundwave. In an interview at the festival with The Pit FM, the band claimed that they intended to record new CKY material with Davies later that year. After a year without CKY news, in March 2013 Margera posted on the "Ask CKY" section of the band's website to assure fans that the status of the group was still unclear, although he also noted that "5 or 6 awesome songs" had been written with Ginsburg and Janaitis which may be released as CKY. In October, Miller made a statement that he had changed his mind about relinquishing the band's moniker, and noted that he would be recording a new CKY album for a 2014 release whether he could reconcile with the other band members or not.


title: CKY (band)

text: In January 2014, Miller and Ginsburg shared a number of recent photos of them together with guitars, indicating a potential reunion for the band. Miller expanded on the news on his Facebook page, revealing that he had reached out to "almost all former members" of the band but was unsure as to who would return, and that he and Ginsburg were working on at least eight songs together. Another update was issued in March, with Miller revealing that he and Ginsburg had "collaborated on a very mellow, melancholy song idea" recently, and that he wanted the new CKY album to serve as the soundtrack to a planned documentary about the band. Miller confirmed on February 12, 2015 that the reconciliation hadn't work out, claiming that working with Ginsburg was "so irritating and so stressful [he] had no choice but to cut the chord". That same day, it was announced that CKY would be performing at Canadian festival Amnesia Rockfest in June. Miller claimed that he knew nothing about the show and Ginsburg asserted that his focus was on his upcoming solo album, although it was confirmed by Bam Margera that Jess would be involved in the show. The band played the festival with Davies returning as frontman. However, Miller also used the CKY moniker (as "CKY + Foreign Objects") for a number of shows booked in 2015 with guitarist Kenneth Hunter, bassist Shaun Luera and drummer Tim Luera. In an interview with "The Sinner's Ball" radio show in August 2015, Miller described his former bandmates as "pathetic sons of bitches" and condemned Davies' performances in the band as "embarrassing". In a later interview in October, Miller claimed that he would be re-recording and re-releasing "An Answer Can Be Found", as well as a new album, under the name MechaCKY (later renamed 96 Bitter Beings).


title: CKY (band)

text: In May 2016, it was confirmed that Ginsburg, Margera and Deis would be continuing as a three-piece CKY (with the guitarist also singing), performing at the Random Hero Festival (in honour of deceased CKY Crew member Ryan Dunn) in Cleveland, Ohio, in June and recording a new album in July at Rancho De La Luna in Joshua Tree, California. The following February, the band announced its first tour as a three-piece, with 12 shows in the UK (their first in the country since 2011) scheduled for May 2017. Due to "popular demand", a second date at London's Camden Underworld was later added to the end of the tour, while several other shows were upgraded to larger venues. The group also performed at all dates on the 2017 Warped Tour, which ran between June 16 and August 6, 2017 and included 41 shows in the United States and Canada. In March 2017, CKY signed a worldwide deal with Entertainment One Music, and released their fifth studio album, "The Phoenix", that June. Throughout October and November 2017, CKY toured the United States as the opening act for HIM on HIM's farewell tour.


title: CKY (band)

text: On June 3, 2019, the band announced that Deis had left the band. In a statement by Deis, the bassist explained that "I'm stepping aside to focus on myself and my family so that CKY can continue their dominant return with nothing holding it back." Former A Life Once Lost bassist Chris Weyh performed with the band for the Vans Warped Tour 25th anniversary show. Ginsburg and Margera performed as a duo using backing tracks for a subsequent European tour. CKY released "Fuck.Shit.Help. & Yeah" featuring late Turbonegro frontman Hank von Hell, alongside Anders Odden, on November 26, 2021.


title: CKY (band)

text: A number of music critics have stated that it as difficult to categorize CKY into a specific musical genre. The band is listed by music website AllMusic in the post-grunge, hard rock, and stoner rock. Due to the band's association with professional skateboarding (owed mainly to its link with Bam Margera), its music has been dubbed as skate punk, but it is suggested by AllMusic's Greg Prato that this label was extinguished upon the release of "Infiltrate•Destroy•Rebuild", which features a "heavy alt-metal sound". The group's sound has been described as stoner metal by "Rolling Stone"s Jenny Eliscu. Writers at both Blabbermouth.net and the Ultimate Guitar Archive have described CKY as "genre-defying", while PopMatters reviewer Nikki Tranter described the sound on "Infiltrate•Destroy•Rebuild" as "impossible to label".


title: CKY (band)

text: CKY's songs have featured references to a number of different lyrical themes. On "Infiltrate•Destroy•Rebuild", it is proposed by Tranter that a number of tracks are written about "the decaying state of humanity" and "the need for some kind of freedom", with the writer describing the lyrics as "relentlessly dark, yet beautifully written, observant and real". On "An Answer Can Be Found", there are multiple songs said to be renouncing the idea of suicide. The band has also written songs as part of ongoing storylines on a number of occasions – "96 Quite Bitter Beings", "Escape from Hellview" and "Hellions on Parade" (as well as an early demo called "Thanks for the Ride") make up a series of songs about a fictional town called Hellview, the residents of which "doesn't take kindly to outsiders", and the songs on "Carver City" tell a story of a town named after a fisherman, who killed his crew and later returns to "curse the city".


title: CKY (band)

text: The fanbase of CKY is affectionately dubbed the CKY Alliance, and has been identified as particularly passionate about the band. Miller has proposed that the Alliance is "almost more important than the band", praising them as instrumental in the band's success. Following the release of "Infiltrate•Destroy•Rebuild", members of the Alliance "bombarded" "Rolling Stone" magazine with "pissed-off e-mails" after it awarded the album two out of five stars in a negative review. After they followed this with another poor review of "An Answer Can Be Found", Miller responded to writer Jenny Eliscu, mocking her as "an aging, ugly skank" and mocking "Rolling Stone" themselves as "predictable, tiresome and unprofessional" to have even employed her. The band's fans followed by waging a "harassment campaign" against her, which included phoning and emailing her with death threats.


title: CKY (band)

text: In reviews of its albums, CKY has received praise from various music critics. Common points of commendation include the band's mix of various musical styles, the guitar performances of Miller and Ginsburg, the group's high production values, and the experimental nature of many songs. Other commentators, however, have identified and criticized a reliance on similar styles for multiple songs – "An Answer Can Be Found", for example, was criticized by a number of sources a lack of progression and invention. A similar sentiment was echoed in relation to "Carver City" by Blabbermouth.net writer Keith Bergman.


title: Conversion of Paul the Apostle

text: The conversion of Paul the Apostle (also the Pauline conversion, Damascene conversion, Damascus Christophany and the "road to Damascus" event) was, according to the New Testament, an event in the life of Saul/Paul the Apostle that led him to cease persecuting early Christians and to become a follower of Jesus.


title: Conversion of Paul the Apostle

text: Paul's conversion experience is discussed in both the Pauline epistles and in the Acts of the Apostles. According to both sources, Saul/Paul was not a follower of Jesus and did not know him before his crucifixion. The narrative of the Book of Acts suggests Paul's conversion occurred 4–7 years after the crucifixion of Jesus. The accounts of Paul's conversion experience describe it as miraculous, supernatural, or otherwise revelatory in nature.


title: Conversion of Paul the Apostle

text: Before his conversion, Paul was known as Saul and was "a Pharisee of Pharisees", who "intensely persecuted" the followers of Jesus. Paul describes his life before conversion in his Epistle to the Galatians:


title: Conversion of Paul the Apostle

text: Paul also discusses his pre-conversion life in his Epistle to the Philippians, 3:4–6, and his participation in the stoning of Stephen is described in Acts 7:57–8:3.


title: Conversion of Paul the Apostle

text: In the Pauline epistles, the description of Paul's conversion experience is brief. The First Epistle to the Corinthians 9:1 and 15:3–8 describes Paul as having seen the risen Christ:


title: Conversion of Paul the Apostle

text: The Second Epistle to the Corinthians also describes Paul's experience of revelation. In verse 1 the NIV translation mentions "revelations from the Lord", but other translations, including the NRSV, translate that phrase as "revelations of the Lord". The passage begins with Paul seeming to speak about another person, but very quickly he makes it clear he is speaking of himself.


title: Conversion of Paul the Apostle

text: The Epistle to the Galatians chapter 1 also describes his conversion as a divine revelation, with Jesus appearing to Paul.


title: Conversion of Paul the Apostle

text: The Acts of the Apostles discusses Paul's conversion experience at three different points in the text, in far more detail than in the accounts in Paul's letters. The Book of Acts says that Paul was on his way from Jerusalem to Syrian Damascus with a mandate issued by the High Priest to seek out and arrest followers of Jesus, with the intention of returning them to Jerusalem as prisoners for questioning and possible execution. The journey is interrupted when Paul sees a blinding light, and communicates directly with a divine voice.


title: Conversion of Paul the Apostle

text: The account continues with a description of Ananias of Damascus receiving a divine revelation instructing him to visit Saul at the house of Judas on the Street Called Straight and there lay hands on him to restore his sight (the house of Judas is traditionally believed to have been near the west end of the street). Ananias is initially reluctant, having heard about Saul's persecution, but obeys the divine command:


title: Conversion of Paul the Apostle

text: Acts' second telling of Paul's conversion occurs in a speech Paul gives when he is arrested in Jerusalem. Paul addresses the crowd and tells them of his conversion, with a description essentially the same as that in Acts 9, but with slight differences. For example, Acts 9:7 notes that Paul's companions did not see who he was speaking to, while Acts 22:9 indicates that they did share in seeing the light (see also Differences between the accounts, below). The speech is clearly tailored for its Jewish audience, with stress being placed in Acts 22:12 on Ananias's good reputation among Jews in Damascus, rather than on his Christianity.


title: Conversion of Paul the Apostle

text: Acts' third discussion of Paul's conversion occurs when Paul addresses King Agrippa, defending himself against the accusations of antinomianism that have been made against him. This account is briefer than the others. The speech here is again tailored for its audience, emphasizing what a Roman ruler would understand: the need to obey a heavenly vision, and reassuring Agrippa that Christians were not a secret society.


title: Conversion of Paul the Apostle

text: An contradiction in the details of the account of Paul's revelatory vision given in Acts has been the subject of some debate. Whereas states that Paul's travelling companions heard the voice, states that they did not. Traditional readings and modern biblical scholarship both see a discrepancy between these passages, but some modern Conservative Evangelical commentators argue that the discrepancy can be explained. Richard Longenecker argues that first century readers might have understood the two passages to mean that everybody heard the sound of the voice, but "only Paul understood the articulated words".


title: Conversion of Paul the Apostle

text: The debate revolves around two Greek words. The noun φωνῆ ("phōnē" - a source of English words such as "telephone", "phonic", and "phoneme") translates as not only "voice, utterance, report, faculty of speech, the call of an animal" but also "sound" when referring to an inanimate object. However, the normal Greek word for an inarticulate sound is ψόφος ("psophos").


title: Conversion of Paul the Apostle

text: The verb ἀκούω ("akouō" - a source of English words such as "acoustics"), which usually means "hear", has the secondary meaning of "understand", which is how most translations render it in , for example. However, this meaning is so rare that the main English-to-Greek dictionaries do not list ἀκούω among the possible translations of "understand". Resolving the discrepancy involves translating φωνῆ and ἀκούω in Acts 9:7 as "hear" and "sound" respectively, but translating the same words in Acts 22:9 as "understand" and "voice".


title: Conversion of Paul the Apostle

text: The New Revised Standard Version (NRSV), which is commonly the preferred translation of biblical scholars and used in the most influential publications in the field, renders the two texts as follows:


title: Conversion of Paul the Apostle

text: Most traditional translations including the English King James Version (KJV), the Latin Vulgate, and Luther's German translation are similar, translating the key words identically in each of the parallel texts, and thus not disguising the contradiciton. However, since the 1970s, some versions have attempted a harmonizing translation, including the New International Version (NIV), which reads:


title: Conversion of Paul the Apostle

text: Likewise the NET Bible and others. By translating φωνῆ and ἀκούω differently in each case, the contradiction is eliminated.


title: Conversion of Paul the Apostle

text: Those who support harmonizing readings sometimes point out that in Acts 9:7, ἀκούω appears in a participle construction with a genitive (ἀκούοντες μὲν τῆς φωνῆς), and in Acts 22:9 as a finite verb with an accusative object (φωνὴν οὐκ ἤκουσαν). Nigel Turner suggests the use of the accusative indicates hearing with understanding. More commonly, proponents of this view have asserted that the genitive is used when a person is heard, the accusative for a thing, which goes in the same direction but yields a far weaker argument. New Testament scholars Daniel B. Wallace and F.F. Bruce find this argument based on case inconclusive and caution against using it. Wallace gathers all examples of ἀκούω with each construction in the New Testament and finds that there are more exceptions to the supposed rule than examples of it. He concludes: "regardless of how one works through the accounts of Paul’s conversion, an appeal to different cases probably ought not to form any part of the solution."


title: Conversion of Paul the Apostle

text: Whereas Protestants saw the conversion as a demonstration of "sola fide", Counter-Reformation Catholics saw it as a demonstration, or at least a metaphor for, the power of preaching, which received a strong new emphasis after the Council of Trent.


title: Conversion of Paul the Apostle

text: The conversion of Paul, in spite of his attempts to completely eradicate Christianity, is seen as evidence of the power of Divine Grace, with "no fall so deep that grace cannot descend to it" and "no height so lofty that grace cannot lift the sinner to it." It also demonstrates "God's power to use everything, even the hostile persecutor, to achieve the divine purpose."


title: Conversion of Paul the Apostle

text: There is no evidence to suggest that Paul arrived on the road to Damascus already with a single, solid, coherent scheme that could form the framework of his mature theology. Instead, the conversion, and the associated understanding of the significance of the resurrection of the crucified Jesus, caused him to rethink from the ground up everything he had ever believed in, from his own identity to his understanding of Second Temple Judaism and who God really was.


title: Conversion of Paul the Apostle

text: The transforming effect of Paul's conversion influenced the clear antithesis he saw "between righteousness based on the law," which he had sought in his former life; and "righteousness based on the death of Christ," which he describes, for example, in the Epistle to the Galatians.


title: Conversion of Paul the Apostle

text: Based on Paul's testimony in Galatians 1 and the accounts in Acts (Acts 9, 22, 26), where it is specifically mentioned that Paul was tasked to be a witness to the Gentiles, it could be interpreted that what happened on the road to Damascus was not just a conversion from first-century Judaism to a faith centred on Jesus Christ, but also a commissioning of Paul as an Apostle to the Gentiles—although in Paul's mind they both amounted to the same thing.


title: Conversion of Paul the Apostle

text: The Acts of the Apostles says that Paul's conversion experience was an encounter with the resurrected Christ. Alternative explanations have been proposed, including sun stroke and seizure. In 1987, D. Landsborough published an article in the "Journal of Neurology, Neurosurgery, and Psychiatry", in which he stated that Paul's conversion experience, with the bright light, loss of normal bodily posture, a message of strong religious content, and his subsequent blindness, suggested "an attack of , perhaps ending in a convulsion ... The blindness which followed may have been post-ictal."


title: Conversion of Paul the Apostle

text: This conclusion was challenged in the same journal by James R. Brorson and Kathleen Brewer, who stated that this hypothesis failed to explain why Paul's companions heard a voice (Acts 9:7), saw a light, or fell to the ground. Additionally, Paul's blindness remitted in sudden fashion, rather than the gradual resolution typical of post-ictal states, and no mention is made of epileptic convulsions; indeed such convulsions may, in Paul's time, have been interpreted as a sign of demonic influence, unlikely in someone accepted as a religious leader.


title: Conversion of Paul the Apostle

text: A 2012 paper in the "Journal of Neuropsychiatry and Clinical Neurosciences" suggested that Paul’s conversion experience might be understood as involving psychogenic events. This occurring in the overall context of Paul’s other auditory and visual experiences that the authors propose may have been caused by mood disorder associated psychotic spectrum symptoms.


title: Conversion of Paul the Apostle

text: Our Blessed Lord prevented Saul with His grace, enlightened his understanding, moved his heart, and prepared his will to do all that was commanded him. In the very midst of his sinful career grace called to Saul to stop, and changed his heart so completely that the bitter enemy of Jesus Christ was transformed into an apostle, all aglow with love; and the persecutor of the Christian faith became its indefatigable defender and advocate. Thus St. Paul was able to say of himself: "By the grace of God I am what I am; and His grace in me hath not been void, but I have laboured more abundantly than they all: yet not I, but the grace of God with me" (1 Cor. 15:10)."


title: Conversion of Paul the Apostle

text: Thomas Aquinas sees Paul's conversion as an example of "a sudden grace of God," writing in his Summa Theologiae:


title: Conversion of Paul the Apostle

text: Since a man cannot prepare himself for grace unless God prevent and move him to good, it is of no account whether anyone arrive at perfect preparation instantaneously, or step by step. For it is written (Ecclus. 11:23): "It is easy in the eyes of God on a sudden to make the poor man rich." Now it sometimes happens that God moves a man to good, but not perfect good, and this preparation precedes grace. But He sometimes moves him suddenly and perfectly to good, and man receives grace suddenly, according to Jn. 6:45: "Every one that hath heard of the Father, and hath learned, cometh to Me." And thus it happened to Paul, since, suddenly when he was in the midst of sin, his heart was perfectly moved by God to hear, to learn, to come; and hence he received grace suddenly.


title: Conversion of Paul the Apostle

text: The subject was not common in medieval art, only usually being painted as one of a number of predella scenes of his life below an altarpiece dedicated to the saint. From the Renaissance it gradually became popular as a subject for larger paintings. Apart from the religious significance, the subject allowed the artist to include landscape elements, a crowd of figures and horses. The drama of the event especially appealed to Baroque painters. It was sometimes paired with the handing of the Keys to Saint Peter, although in the Vatican Cappella Paolina Michelangelo paired it with Peter's "Crucifixion" in the 1540s, perhaps in a change to the original plan.


title: Conversion of Paul the Apostle

text: The conversion of Paul has been depicted by many artists, including Albrecht Dürer, Francisco Camilo, Giovanni Bellini, Fra Angelico, Fra Bartolomeo, Pieter Bruegel the Elder, William Blake, Luca Giordano, Sante Peranda, and Juan Antonio de Frías y Escalante. Michelangelo's fresco "The Conversion of Saul" is in the Cappella Paolina of the Vatican Palace.


title: Conversion of Paul the Apostle

text: The Renaissance Italian master Caravaggio painted two works depicting the event: "The Conversion of Saint Paul" and "Conversion on the Way to Damascus". Peter Paul Rubens also produced several works on the theme.


title: Conversion of Paul the Apostle

text: A large number of the many depictions show Paul, and often several of his companions, travelling the Damascus Road on horseback, Paul most often on a white horse. This is not mentioned in the biblical accounts (which do not say how he travelled), and certainly makes for a more dramatic composition. The horses are usually shown as disturbed by the sudden appearance of the vision, and have often fallen to the ground themselves. It may also reflect how people of the various periods expected a person of Paul's importance to travel a distance of 135 miles (or 218 km). Perhaps first appearing in the 14th century, Paul's horse appears in the most important depictions from the 15th century onwards.


title: Conversion of Paul the Apostle

text: Chapter seventeen of Ralph Ellison's 1952 novel "Invisible Man" includes a literary device related to the Saul to Paul conversion: "'You start Saul, and end up Paul,' my grandfather had often said. 'When you're a youngun, you Saul, but let life whup your head a bit and you starts to trying to be Paul – though you still Sauls around on the side.'"


title: Conversion of Paul the Apostle

text: The conversion of Paul is the main term of argument of Felix Mendelssohn Bartholdy's oratorio "Paulus" (St. Paul), MWV A 14 / Op. 36] (1833–36). It is also subject of the choral motet "Saule, Saule, quid me persequeris" by Giaches de Wert (1535–1596). It is also the focus of an eight part mixed choir a cappella piece (The Conversion of Saul) composed by Z. Randall Stroope.


title: Conversion of Paul the Apostle

text: From the conversion of Paul, we get the metaphorical reference to the "Road to Damascus" that has come to refer to a sudden or radical conversion of thought or a change of heart or mind even in matters outside of a Christian context. For example, Australian politician Tony Abbott was described as having been "on his own road to Damascus" after pledging increased mental health funding, and a New Zealand drug dealer turned police officer was likewise described as taking "the first step on the road to Damascus." In science fiction, the book "Road to Damascus" is based on a sudden political conversion of a self-aware tank, Unit SOL-0045, "Sonny," a Mark XX Bolo, on the battlefield.


title: Conversion of Paul the Apostle

text: In "-30-", the finale episode of "The Wire", Norman Wilson tells Mayor Tommy Carcetti the Jimmy McNulty/Lester Freamon "serial killer" hoax is the mayor's "road to Damascus" moment and likens the detectives' fabrication of a serial killer, which allows them to successfully fund and achieve their actual investigative goals, to Carcetti's adoption of popular campaign platforms he doesn't really care about in order to achieve his actual political agenda. Similar parallel can be drawn to the compromises and decisions made by other entities who've taken shortcuts or otherwise "juked" the data to achieve their ends, such as the "Baltimore Sun"s managing editors in their pursuit of a Pulitzer Prize.


title: Conversion of Paul the Apostle

text: In Episode 3, Season 4 of "Downton Abbey", Lady Grantham referred to Lord Grantham’s change of heart towards his daughter Edith’s boyfriend as a Damascene Conversion.


title: Conversion of Paul the Apostle

text: The Feast of the Conversion of Saint Paul the Apostle is a feast celebrated during the liturgical year on 25 January, recounting the conversion. This feast is celebrated in the Roman Catholic, Anglican and Lutheran churches. This feast is at the conclusion of the Week of Prayer for Christian Unity, an international Christian ecumenical observance that began in 1908, which is an octave (an eight-day observance) spanning from 18 January (observed in Anglican and Lutheran tradition as the Confession of Peter, and in the pre-1961 Roman Catholic Church as the feast of the Chair of Saint Peter at Rome) to 25 January. In rural England, the day functioned much like groundhog day does in the modern-day United States. Supposed prophecies ranged from fine days predicting good harvests, to clouds and mists signifying pestilence and war in the coming months.


title: Gene therapy

text: Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DNA was performed in 1980, by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989. The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990. It is thought to be able to cure many genetic disorders or treat them over time.


title: Gene therapy

text: Between 1989 and December 2018, over 2,900 clinical trials were conducted, with more than half of them in phase I. As of 2017, Spark Therapeutics' Luxturna (RPE65 mutation-induced blindness) and Novartis' Kymriah (Chimeric antigen receptor T cell therapy) are the FDA's first approved gene therapies to enter the market. Since that time, drugs such as Novartis' Zolgensma and Alnylam's Patisiran have also received FDA approval, in addition to other companies' gene therapy drugs. Most of these approaches utilize adeno-associated viruses (AAVs) and lentiviruses for performing gene insertions, "in vivo" and "ex vivo", respectively. AAVs are characterized by stabilizing the viral capsid, lower immunogenicity, ability to transduce both dividing and nondividing cells, the potential to integrate site specifically and to achieve long-term expression in the in-vivo treatment. (Gorell et al. 2014) ASO / siRNA approaches such as those conducted by Alnylam and Ionis Pharmaceuticals require non-viral delivery systems, and utilize alternative mechanisms for trafficking to liver cells by way of GalNAc transporters.


title: Gene therapy

text: The concept of gene therapy is to fix a genetic problem at its source. If, for instance, a mutation in a certain gene causes the production of a dysfunctional protein resulting (usually recessively) in an inherited disease, gene therapy could be used to deliver a copy of this gene that does not contain the deleterious mutation and thereby produces a functional protein. This strategy is referred to as gene replacement therapy and is employed to treat inherited retinal diseases.


title: Gene therapy

text: While the concept of gene replacement therapy is mostly suitable for recessive diseases, novel strategies have been suggested that are capable of also treating conditions with a dominant pattern of inheritance.


title: Gene therapy

text: Not all medical procedures that introduce alterations to a patient's genetic makeup can be considered gene therapy. Bone marrow transplantation and organ transplants in general have been found to introduce foreign DNA into patients.


title: Gene therapy

text: Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.


title: Gene therapy

text: The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980. Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified and even if he is correct, it's unlikely it produced any significant beneficial effects treating beta thalassemia.


title: Gene therapy

text: After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashanthi DeSilva was treated for ADA-SCID.


title: Gene therapy

text: The first somatic treatment that produced a permanent genetic change was initiated in 1993. The goal was to cure malignant brain tumors by using recombinant DNA to transfer a gene making the tumor cells sensitive to a drug that in turn would cause the tumor cells to die.


title: Gene therapy

text: The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations. The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene. The polymer molecule is packaged within a "vector", which carries the molecule inside cells.


title: Gene therapy

text: Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although , it was still largely an experimental technique. These include treatment of retinal diseases Leber's congenital amaurosis and choroideremia, X-linked SCID, ADA-SCID, adrenoleukodystrophy, chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), multiple myeloma, haemophilia, and Parkinson's disease. Between 2013 and April 2014, US companies invested over $600 million in the field.


title: Gene therapy

text: The first commercial gene therapy, Gendicine, was approved in China in 2003, for the treatment of certain cancers. In 2011, Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia.


title: Gene therapy

text: In 2012, Glybera, a treatment for a rare inherited disorder, lipoprotein lipase deficiency, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.


title: Gene therapy

text: Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered – replacing or disrupting defective genes. Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.


title: Gene therapy

text: DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein. Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome. Naked DNA approaches have also been explored, especially in the context of vaccine development.


title: Gene therapy

text: Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.


title: Gene therapy

text: Gene editing is a potential approach to alter the human genome to treat genetic diseases, viral diseases, and cancer. these approaches are being studied in clinical trials.


title: Gene therapy

text: In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.


title: Gene therapy

text: Over 600 clinical trials utilizing SCGT are underway in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.


title: Gene therapy

text: In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism's cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations and higher risks versus SCGT. The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).


title: Gene therapy

text: The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).


title: Gene therapy

text: In order to replicate, viruses introduce their genetic material into the host cell, tricking the host's cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell. Scientists exploit this by substituting a virus's genetic material with therapeutic DNA or RNA. A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus. Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host's genome, becoming a permanent part of the host's DNA in infected cells.


title: Gene therapy

text: Non-viral vectors for gene therapy present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Newer technologies offer promise of solving these problems, with the advent of increased cell-specific targeting and subcellular trafficking control.


title: Gene therapy

text: Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.


title: Gene therapy

text: More recent approaches, such as those performed by companies such as Ligandal, offer the possibility of creating cell-specific targeting technologies for a variety of gene therapy modalities, including RNA, DNA and gene editing tools such as CRISPR. Other companies, such as Arbutus Biopharma and Arcturus Therapeutics, offer non-viral, non-cell-targeted approaches that mainly exhibit liver trophism. In more recent years, startups such as Sixfold Bio, GenEdit, and Spotlight Therapeutics have begun to solve the non-viral gene delivery problem. Non-viral techniques offer the possibility of repeat dosing and greater tailorability of genetic payloads, which in the future will be more likely to take over viral-based delivery systems.


title: Gene therapy

text: Companies such as Editas Medicine, Intellia Therapeutics, CRISPR Therapeutics, Casebia, Cellectis, Precision Biosciences, bluebird bio, and Sangamo have developed non-viral gene editing techniques, however frequently still use viruses for delivering gene insertion material following genomic cleavage by guided nucleases. These companies focus on gene editing, and still face major delivery hurdles.


title: Gene therapy

text: BioNTech, Moderna Therapeutics and CureVac focus on delivery of mRNA payloads, which are necessarily non-viral delivery problems.


title: Gene therapy

text: Alnylam, Dicerna Pharmaceuticals, and Ionis Pharmaceuticals focus on delivery of siRNA (antisense oligonucleotides) for gene suppression, which also necessitate non-viral delivery systems.


title: Gene therapy

text: In academic contexts, a number of laboratories are working on delivery of PEGylated particles, which form serum protein coronas and chiefly exhibit LDL receptor mediated uptake in cells "in vivo".


title: Gene therapy

text: In in vivo gene therapy, a vector (typically, a virus) is introduced to the patient, which then achieves the desired biological effect by passing the genetic material (e.g. for a missing protein) into the patient's cells. In ex vivo gene therapies, such as CAR-T therapeutics, the patient's own cells (autologous) or healthy donor cells (allogeneic) are modified outside the body (hence, ex vivo) using a vector to express a particular protein, such as a chimeric antigen receptor.


title: Gene therapy

text: In vivo gene therapy is seen as simpler, since it does not require the harvesting of mitotic cells. However, ex vivo gene therapies are better tolerated and less associated with severe immune responses. The death of Jesse Gelsinger in a trial of an adenovirus-vectored treatment for ornithine transcarbamylase deficiency due to a systemic inflammatory reaction led to a temporary halt on gene therapy trials across the United States. , in vivo and ex vivo therapeutics are both seen as safe.


title: Gene therapy

text: Athletes may adopt gene therapy technologies to improve their performance. Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.


title: Gene therapy

text: Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases. For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery. Another theorist claims that moral concerns limit but do not prohibit germline engineering.


title: Gene therapy

text: A recent issue of the journal "Bioethics" was devoted to moral issues surrounding germline genetic engineering in people.


title: Gene therapy

text: Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Association's Council on Ethical and Judicial Affairs stated that "genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics."


title: Gene therapy

text: As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools, and such concerns have continued as technology progressed. With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited. In April 2015, researchers sparked controversy when they reported results of basic research to edit the DNA of non-viable human embryos using CRISPR. A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017 once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."


title: Gene therapy

text: Gene therapy approaches to replace a faulty gene with a healthy gene have been proposed and are being studied for treating some genetic diseases. Diseases such as sickle cell disease that are caused by autosomal recessive disorders for which a person's normal phenotype or cell function may be restored in cells that have the disease by a normal copy of the gene that is mutated, may be a good candidate for gene therapy treatment. The risks and benefits related to gene therapy for sickle cell disease are not known.


title: Gene therapy

text: Some genetic therapies have been approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and for use in Russia and China.


title: Gene therapy

text: Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger, who died in 1999, because of immune rejection response. One X-SCID patient died of leukemia in 2003. In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.


title: Gene therapy

text: Regulations covering genetic modification are part of general guidelines about human-involved biomedical research. There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.


title: Gene therapy

text: The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association's General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001, provides a legal baseline for all countries. HUGO's document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.


title: Gene therapy

text: No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH's Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.


title: Gene therapy

text: NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.


title: Gene therapy

text: An NIH advisory committee published a set of guidelines on gene manipulation. The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient. The protocol for a gene therapy clinical trial must be approved by the NIH's Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.


title: Gene therapy

text: As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.


title: Gene therapy

text: In 1972, Friedmann and Roblin authored a paper in "Science" titled "Gene therapy for human genetic disease?". Rogers (1970) was cited for proposing that "exogenous good DNA" be used to replace the defective DNA in those with genetic defects.


title: Gene therapy

text: In 1984, a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.


title: Gene therapy

text: The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson. Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with adenosine deaminase deficiency (ADA-SCID), a severe immune system deficiency. The defective gene of the patient's blood cells was replaced by the functional variant. Ashanti's immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.


title: Gene therapy

text: Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993). The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocol no.1602 24 November 1993, and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.


title: Gene therapy

text: In 1992, Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases. In 2002, this work led to the publication of the first successful gene therapy treatment for ADA-SCID. The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.


title: Gene therapy

text: In 1993, Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother's placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.


title: Gene therapy

text: Jesse Gelsinger's death in 1999 impeded gene therapy research in the US. As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.


title: Gene therapy

text: The modified gene therapy strategy of antisense IGF-I RNA (NIH n˚ 1602) using antisense / triple helix anti-IGF-I approach was registered in 2002, by Wiley gene therapy clinical trial - n˚ 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n˚ LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.


title: Gene therapy

text: Sickle cell disease can be treated in mice. The mice – which have essentially the same defect that causes human cases – used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.


title: Gene therapy

text: A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.


title: Gene therapy

text: Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.


title: Gene therapy

text: In 2003, a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the blood–brain barrier.


title: Gene therapy

text: Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.


title: Gene therapy

text: Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.


title: Gene therapy

text: In March, researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.


title: Gene therapy

text: In May, a team reported a way to prevent the immune system from rejecting a newly delivered gene. Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.


title: Gene therapy

text: In August, scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.


title: Gene therapy

text: In November, researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.


title: Gene therapy

text: In May, researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.


title: Gene therapy

text: Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April. Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May, two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.


title: Gene therapy

text: In September researchers were able to give trichromatic vision to squirrel monkeys. In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.


title: Gene therapy

text: An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.


title: Gene therapy

text: In September it was announced that an 18-year-old male patient in France with beta thalassemia major had been successfully treated. Beta thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions. The technique used a lentiviral vector to transduce the human β-globin gene into purified blood and marrow cells obtained from the patient in June 2007. The patient's haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed. Further clinical trials were planned. Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.


title: Gene therapy

text: Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).


title: Gene therapy

text: In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011. It required complete ablation of existing bone marrow, which is very debilitating.


title: Gene therapy

text: In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease. In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.


title: Gene therapy

text: Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.


title: Gene therapy

text: In 2011, Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF. Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.


title: Gene therapy

text: The FDA approved Phase I clinical trials on thalassemia major patients in the US for 10 participants in July. The study was expected to continue until 2015.


title: Gene therapy

text: In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis. The recommendation was endorsed by the European Commission in November 2012, and commercial rollout began in late 2014. Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012, revised to $1 million in 2015, making it the most expensive medicine in the world at the time. , only the patients treated in clinical trials and a patient who paid the full price for treatment have received the drug.


title: Gene therapy

text: In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.


title: Gene therapy

text: In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B cells, cancerous or not. The researchers believed that the patients' immune systems would make normal T cells and B cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.


title: Gene therapy

text: Following encouraging Phase I trials, in April, researchers announced they were starting Phase II clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function. The U.S. Food and Drug Administration (FDA) granted this a breakthrough therapy designation to accelerate the trial and approval process. In 2016, it was reported that no improvement was found from the CUPID 2 trial.


title: Gene therapy

text: In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 7–32 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills. The other children had Wiskott–Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer. Follow up trials with gene therapy on another six children with Wiskott–Aldrich syndrome were also reported as promising.


title: Gene therapy

text: In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress. In 2014, a further 18 children with ADA-SCID were cured by gene therapy. ADA-SCID children have no functioning immune system and are sometimes known as "bubble children".


title: Gene therapy

text: Also in October researchers reported that they had treated six people with haemophilia in early 2011 using an adeno-associated virus. Over two years later all six were producing clotting factor.


title: Gene therapy

text: In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1. Over a six-month to two-year period all had improved their sight. By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting. Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.


title: Gene therapy

text: In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.


title: Gene therapy

text: In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.


title: Gene therapy

text: In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys' cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.


title: Gene therapy

text: In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing "scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans" until the full implications "are discussed among scientific and governmental organizations".


title: Gene therapy

text: In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies but that basic research including embryo gene editing should continue.


title: Gene therapy

text: Researchers successfully treated a boy with epidermolysis bullosa using skin grafts grown from his own skin cells, genetically altered to repair the mutation that caused his disease.


title: Gene therapy

text: In November, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]). Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.


title: Gene therapy

text: In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis and the European Commission approved it in June. This treats children born with adenosine deaminase deficiency and who have no functioning immune system. This was the second gene therapy treatment to be approved in Europe.


title: Gene therapy

text: In October, Chinese scientists reported they had started a trial to genetically modify T cells from 10 adult patients with lung cancer and reinject the modified T cells back into their bodies to attack the cancer cells. The T cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.


title: Gene therapy

text: A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.


title: Gene therapy

text: In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced non-Hodgkin lymphoma.


title: Gene therapy

text: In March, French scientists reported on clinical research of gene therapy to treat sickle cell disease.


title: Gene therapy

text: In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia. Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or "CAR-T") that reacts to the cancer, and are administered back to the person. The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.


title: Gene therapy

text: In October, biophysicist and biohacker Josiah Zayner claimed to have performed the very first in-vivo human genome editing in the form of a self-administered therapy.


title: Gene therapy

text: On 13 November, medical scientists working with Sangamo Therapeutics, headquartered in Richmond, California, announced the first ever in-body human gene editing therapy. The treatment, designed to permanently insert a healthy version of the flawed gene that causes Hunter syndrome, was given to 44-year-old Brian Madeux and is part of the world's first study to permanently edit DNA inside the human body. The success of the gene insertion was later confirmed. Clinical trials by Sangamo involving gene editing using zinc finger nuclease (ZFN) are ongoing.


title: Gene therapy

text: In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient's blood clotting levels.


title: Gene therapy

text: In December, the FDA approved Luxturna, the first "in vivo" gene therapy, for the treatment of blindness due to Leber's congenital amaurosis. The price of this treatment is for both eyes.


title: Gene therapy

text: In May, the FDA approved onasemnogene abeparvovec (Zolgensma) for treating spinal muscular atrophy in children under two years of age. The list price of Zolgensma was set at per dose, making it the most expensive drug ever.


title: Gene therapy

text: In May, the EMA approved betibeglogene autotemcel (Zynteglo) for treating beta thalassemia for people twelve years of age and older.


title: Gene therapy

text: In July, Allergan and Editas Medicine announced phase I/II clinical trial of AGN-151587 for the treatment of Leber congenital amaurosis 10. This is the first study of a CRISPR-based "in vivo" human gene editing therapy, where the editing takes place inside the human body. The first injection of the CRISPR-Cas System was confirmed in March 2020.


title: Gene therapy

text: In May, onasemnogene abeparvovec (Zolgensma) was approved by the European Union for the treatment of spinal muscular atrophy in people who either have clinical symptoms of SMA type 1 or who have no more than three copies of the "SMN2" gene, irrespective of body weight or age.


title: Gene therapy

text: In August, Audentes Therapeutics reported that three out of 17 children with X-linked myotubular myopathy participating the clinical trial of a AAV8-based gene therapy treatment AT132 have died. It was suggested that the treatment, whose dosage is based on body weight, exerts a disproportionately toxic effect on heavier patients, since the three patients who died were heavier than the others. The trial has been put on clinical hold.


title: Gene therapy

text: On 15 October, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A gene), a gene therapy for the treatment of children with the "late infantile" (LI) or "early juvenile" (EJ) forms of metachromatic leukodystrophy (MLD). The active substance of Libmeldy consists of the child's own stem cells which have been modified to contain working copies of the ARSA gene. When the modified cells are injected back into the patient as a one-time infusion, the cells are expected to start producing the ARSA enzyme that breaks down the build-up of sulfatides in the nerve cells and other cells of the patient's body. Libmeldy was approved for medical use in the EU in December 2020.


title: Gene therapy

text: On 15 October, Lysogene, a French biotechnological company, reported the death of a patient in who has received LYS-SAF302, an experimental gene therapy treatment for mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A).


title: Gene therapy

text: In May, a new method using an altered version of the HIV virus as a lentivirus vector was reported in the treatment of 50 children with ADA-SCID obtaining positive results in 48 of them, this method is expected to be safer than retroviruses vectors commonly used in previous studies of SCID where the development of leukemia was usually observed and had already been used in 2019, but in a smaller group with X-SCID.


title: Gene therapy

text: In June a clinical trial on six patients affected with transthyretin amyloidosis reported a reduction the concentration of missfolded transthretin (TTR) protein in serum through CRISPR-based inactivation of the "TTR" gene in liver cells observing mean reductions of 52% and 87% among the lower and higher dose groups.This was done in vivo without taking cells out of the patient to edit them and reinfuse them later.


title: Gene therapy

text: In July results of a small gene therapy phase I study was published reporting observation of dopamine restoration on seven patients between 4 and 9 years old affected by aromatic L-amino acid decarboxylase deficiency (AADC deficiency).


title: Gene therapy

text: In February, the first ever gene therapy for Tay–Sachs disease was announced, it uses an adeno-associated virus to deliver the correct instruction for the HEXA gene on brain cells which causes the disease. Only two children were part of a compassionate trial presenting improvements over the natural course of the disease and no vector-related adverse events.


title: Gene therapy

text: In July results of a gene therapy candidate for haemophilia B called FLT180 were announced, it works using an adeno-associated virus (AAV) to restore the clotting factor IX (FIX) protein, normal levels of the protein were observed with low doses of the therapy but immunosuppression was necessitated to decrease the risk of vector-related immune responses.


title: Gene therapy

text: In December, a 13-year girl that had been diagnosed with T-cell acute lymphoblastic leukaemia was successfully treated at Great Ormond Street Hospital (GOSH) in the first documented use of therapeutic gene editing for this purpose, after undergoing six months of an experimental treatment, where all attempts of other treatments failed. The procedure included reprogramming a healthy T-cell to destroy the cancerous T-cells to first rid her of leukaemia, and then rebuilding her immune system using healthy immune cells. The GOSH team used BASE editing and had previously treated a case of acute lymphoblastic leukaemia in 2015 using TALENs.


title: Kharkiv Oblast

text: Kharkiv Oblast (), also referred to as Kharkivshchyna (), is an oblast (province) of eastern Ukraine. The oblast borders Russia to the north, Luhansk Oblast to the east, Donetsk Oblast to the south-east, Dnipropetrovsk Oblast to the south-west, Poltava Oblast to the west and Sumy Oblast to the north-west. The area of the oblast is 31,400 km², corresponding to 5.2% of the total territory of Ukraine.


title: Kharkiv Oblast

text: The oblast is the third most populous province of Ukraine, with a population of 2,633,834 in 2021, more than half (1.43 million) of whom live in the city of Kharkiv, the oblast's administrative center. While the Russian language is primarily spoken in the cities of Kharkiv oblast, elsewhere in the oblast most inhabitants speak Ukrainian.


title: Kharkiv Oblast

text: The oblast borders Russia (Belgorod Oblast) to the north, Luhansk Oblast to the east, Donetsk Oblast to the south-east, Dnipropetrovsk Oblast to the south-west, Poltava Oblast to the west and Sumy Oblast to the north-west.


title: Kharkiv Oblast

text: During the Soviet administrative reform of 1923–1929, in 1925, the Kharkov Governorate was abolished leaving its five okruhas: Okhtyrka (originally Bohodukhiv), Izyum, Kupyansk, Sumy, and Kharkiv. Introduced in the Soviet Union in 1923, a similar subdivisions existed in Ukraine back in 1918. In 1930 all okruhas were also abolished with raions becoming the first level of subdivision of Ukraine until 1932.


title: Kharkiv Oblast

text: The modern Kharkiv Oblast was established on 27 February 1932. In the summer of 1932, some parts of the oblast were included in the newly created Donetsk Oblast originally centered in Artemivsk (later in Stalino). Then in the fall, some territories of the Kharkiv Oblast were used in creation of Chernihiv Oblast. More territories became part of Poltava Oblast in fall of 1937 and Sumy Oblast in winter of 1939.


title: Kharkiv Oblast

text: During the Holodomor the population of the Kharkiv Oblast together with Kyiv Oblast suffered the most. The region saw major fighting during World War II in several Battles of Kharkov between 1941 and 1943.


title: Kharkiv Oblast

text: During the 1991 referendum, 86.33% of votes in Kharkiv Oblast were in favor of the Declaration of Independence of Ukraine. A survey conducted in December 2014 by the Kyiv International Institute of Sociology found 4.2% of the oblast's population supported their region joining Russia, 71.5% did not support the idea, and the rest were undecided or did not respond.


title: Kharkiv Oblast

text: During the 2022 Russian invasion of Ukraine, the Russian military launched a major military offensive in the region — the Eastern Ukraine offensive — which resulted in the occupation of parts of the oblast. By late August, about one third of the territory of Kharkiv Oblast was occupied including Izum and Kupiansk. In July 2022, the Donetsk People's Republic signed a memorandum to "liberate Kharkiv from Ukraine".


title: Kharkiv Oblast

text: In early September 2022, the Ukrainian military commenced a counteroffensive in the region. Several settlements in the region were recaptured from Russian control. By 10 September 2022, Ukraine had recaptured Kupiansk and Izium. On 11 September, Russia had retreated from many of the settlements it previously occupied in the oblast and the Russian Ministry of Defense announced a formal withdrawal of Russian forces from most of Kharkiv Oblast stating that an "operation to curtail and transfer troops" was underway." By 12 September 2022, as the Russian front lines in Kharkiv Oblast continued to collapse, Ukrainian forces had managed to push back to the north-eastern border with Russia in some areas of the region. By 3 October 2022, Russian forces had almost completely withdrawn from Kharkiv Oblast.


title: Kharkiv Oblast

text: Its population in 2001 was 2,895,800 million (1,328,900 males (45.9%) and 1,566,900 females (54.1%)).


title: Kharkiv Oblast

text: The Kharkiv Oblast is administratively subdivided into 7 raions (districts). Prior to the 2020 decentralization reform, there were 25 raions, and also 7 cities (municipalities) that were directly subordinate to the oblast government (Chuhuiv, Izium, Kupiansk, Liubotyn, Lozova, Pervomaiskyi, and the administrative center of the oblast, Kharkiv).


title: Kharkiv Oblast

text: Most of Ukraine's oblasts are named after their capital cities, officially called "oblast centers" (, translit. "oblasnyi tsentr"). The name of each oblast is a relative adjective, formed by adding a feminine suffix to the name of respective center city: "Kharkiv" is the center of the "Kharkivs’ka oblast’" (Kharkiv Oblast). Most oblasts are also sometimes referred to in a feminine noun form, following the convention of traditional regional place names, ending with the suffix "-shchyna", as is the case with the Kharkiv Oblast, "Kharkivshchyna".


title: Kharkiv Oblast

text: The Kharkiv oblast has a primarily industrial economy, including engineering, metallurgy, manufacturing, production of chemicals and food processing. It also has an important agricultural sector with 19,000 square kilometres of arable land (comprising 5.9% of the total arable lands of Ukraine). Agricultural production grew substantially in 2015.


title: Kharkiv Oblast

text: Also in Kharkiv is the airplane plant for space controlling systems. It is a major center for all branches of engineering, from large-scale manufacture to microelectronics. Also situated in Kharkiv Oblast is a gas field, which is one of the biggest in Ukraine.


title: Earliest known life forms

text: Earth remains the only place in the universe known to harbor life. The origin of life on Earth was at least 3.77 billion years ago, possibly as early as 4.28 billion years ago. The Earth's biosphere extends down to at least below the surface, and up to at least into the atmosphere, and includes soil, hydrothermal vents, and rock. Further, the biosphere has been found to extend at least below the ice of Antarctica, and includes the deepest parts of the ocean, down to rocks kilometers below the sea floor. In July 2020, marine biologists reported that aerobic microorganisms (mainly), in "quasi-suspended animation", were found in organically-poor sediments, up to 101.5 million years old, below the seafloor in the South Pacific Gyre (SPG) ("the deadest spot in the ocean"), and could be the longest-living life forms ever found. Under certain test conditions, life forms have been observed to survive in the vacuum of outer space. More recently, in August 2020, bacteria were found to survive for three years in outer space, according to studies conducted on the International Space Station. The total mass of the biosphere has been estimated to be as much as 4 trillion tons of carbon. According to one researcher, "You can find microbes everywhere – [they are] extremely adaptable to conditions, and survive wherever they are."


title: Earliest known life forms

text: Of all species of life forms that ever lived on Earth, over five billion, more than 99% are estimated to be extinct. Some estimates on the number of Earth's current species range from 10 million to 14 million, of which about 1.2 million have been documented and over 86 percent remain undescribed. However, a May 2016 scientific report estimates 1 trillion species currently on Earth, with only one-thousandth of one percent described. Additionally, there are an estimated 10 nonillion (10 to the 31st power) individual viruses (including the related virions) on Earth, the most numerous type of biological entity, which some biologists consider to be life forms.


title: Earliest known life forms

text: The age of Earth is about 4.54 billion years; the earliest undisputed evidence of life on Earth dates from at least 3.5 billion years ago. Some computer models suggest life began as early as 4.5 billion years ago.


title: Earliest known life forms

text: 3.465-billion-year-old Australian Apex chert rocks may once have contained microorganisms, the earliest fossil evidence of life on Earth. Microbial mat fossils have been found in 3.48 billion-year-old sandstone in Western Australia. Evidence of biogenic graphite, and possibly stromatolites, were discovered in 3.7 billion-year-old metasedimentary rocks in southwestern Greenland. Potential "remains of life" were found in 4.1 billion-year-old rocks in Western Australia. "Putative filamentous microfossils", possibly of methanogens and/or methanotrophs, that lived about 3.42-billion-year-old in "a paleo-subseafloor hydrothermal vein system of the Barberton greenstone belt have been identified in South Africa."


title: Earliest known life forms

text: Fossilized microorganisms (microfossils) have been found in hydrothermal vent precipitates from an ancient sea-bed in the Nuvvuagittuq Belt of Quebec, Canada. These may be as old as 4.28 billion years, the oldest evidence of life on Earth, suggesting "an almost instantaneous emergence of life" after ocean formation 4.41 billion years ago. Some researchers even speculate that life may have started nearly 4.5 billion years ago. According to biologist Stephen Blair Hedges, "If life arose relatively quickly on Earth ... then it could be common in the universe". The possibility that terrestrial life forms may have been seeded from outer space has been considered. In January 2018, a study found that 4.5 billion-year-old meteorites found on Earth contained liquid water along with prebiotic complex organic substances that may be ingredients for life.


title: Earliest known life forms

text: As for life on land, in 2019 scientists reported the discovery of a fossilized fungus, named "Ourasphaira giraldae", in the Canadian Arctic, that may have grown on land a billion years ago, well before plants are thought to have been living on land. In July 2018, scientists reported that the earliest life on land may have been bacteria 3.22 billion years ago. In May 2017, evidence of microbial life on land may have been found in 3.48 billion-year-old geyserite in the Pilbara Craton of Western Australia.


title: Earliest known life forms

text: By comparing the genomes of modern organisms (in the domains Bacteria and Archaea), it is possible to infer the existence and age of the last universal common ancestor (LUCA), and a minimal set of genes. A molecular clock model suggests that the LUCA may have lived 4.477 to 4.519 billion years ago, within the Hadean eon.


title: Zoot Suit Riots

text: The Zoot Suit Riots were a series of riots that took place from June 3–8, 1943 in Los Angeles, California, United States, involving American servicemen stationed in Southern California and young Latino and Mexican American city residents. It was one of the dozen wartime industrial cities that suffered race-related riots in the summer of 1943, along with Mobile, Alabama; Beaumont, Texas; Detroit, Michigan; and New York City.


title: Zoot Suit Riots

text: American servicemen and white Angelenos attacked and stripped children, teenagers, and youths who wore zoot suits, ostensibly because they considered the outfits, which were made from large amounts of fabric, to be unpatriotic during World War II. Rationing of fabrics and certain foods was required at the time for the war effort. While most of the violence was directed toward Mexican American youth, African American and Filipino American youths who were wearing zoot suits were also attacked.


title: Zoot Suit Riots

text: The Zoot Suit Riots were related to fears and hostilities aroused by the coverage of the Sleepy Lagoon murder trial, following the killing of a young Latino man in what was then an unincorporated commercial area near Los Angeles. The riot appeared to trigger similar attacks that year against Latinos in Chicago, San Diego, Oakland, Evansville, Philadelphia, and New York City. The defiance of zoot suiters became inspirational for Chicanos during the Chicano Movement.


title: Zoot Suit Riots

text: California was a part of Mexico for 27 years, and part of the Viceroyalty of New Spain for centuries, before becoming part of the United States. Because of this history, there has always been a large Latino population in California. During the early 20th century, many Mexicans immigrated for work to US border states which needed workers, areas such as Texas, Arizona, and California. They were recruited by farmers for work on the large farms and also worked in those states in non-agricultural jobs.


title: Zoot Suit Riots

text: During the Great Depression, in the early 1930s, the United States deported between 500,000 and 2 million people of Mexican descent (including the illegal expulsion of up to 1.2 million U.S. citizens) to Mexico (see Mexican Repatriation), in order to reduce demands on limited American economic resources. By the late 1930s, about three million Mexican Americans resided in the United States. Los Angeles had the highest concentration of ethnic Mexicans outside Mexico.


title: Zoot Suit Riots

text: Job discrimination in Los Angeles forced minorities to work for below-poverty level wages. The Los Angeles newspapers described Mexicans with racially inflammatory propaganda, suggesting a problem with juvenile delinquency. These factors caused much racial tension between Mexican immigrants, those of Mexican descent, and European Americans.


title: Zoot Suit Riots

text: During this time, Los Angeles was undergoing an expansion, which caused disruptions in communal sites, family sites, and family patterns of social interactions due to poor city planning. One major decision was to put a million-dollar Naval training school for the Naval Reserve Armory in the Chavez Ravine, a primarily working-class and immigrant area for Mexican-Americans. As young Mexican-American men from the neighborhood began attacking the ideals of white privilege through a campaign of harassment, intimidation, and resistance a year prior to the riots, the Chavez Ravine area would later be a hot spot for encounters between the zoot suiters and sailors.


title: Zoot Suit Riots

text: Lalo Guerrero became known as the father of Chicano music, as young people adopted music, language, and dress of their own. Young men wore zoot suits—a flamboyant long jacket with baggy pegged pants, sometimes accessorized with a pork pie hat, a long watch chain, and thick-soled shoes. They called themselves ""pachucos"." In the early 1940s, arrests of Mexican-American youths and negative stories in the "Los Angeles Times" fueled a perception that these pachuco gangs were delinquents who were a threat to the broader community.


title: Zoot Suit Riots

text: In the summer of 1942, the Sleepy Lagoon murder case made national news. Nine teenage members of the 38th Street Gang were accused of murdering a civilian man named José Díaz in an abandoned quarry pit. The nine defendants were convicted at trial and sentenced to long prison terms. Eduardo Obregón Pagán wrote:


title: Zoot Suit Riots

text: Many Angelenos saw the death of José Díaz as a tragedy that resulted from a larger pattern of lawlessness and rebellion among Mexican American youths, discerned through their self-conscious fashioning of difference, and increasingly called for stronger measures to crack down on juvenile delinquency.


title: Zoot Suit Riots

text: The convictions of the nine young men were ultimately overturned, but the case generated much animosity within the United States toward Mexican Americans. The police and press characterized all Mexican youths as "pachuco hoodlums and baby gangsters".