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Alexandria's second major success was won by the nephew and successor of Theophilus, St Cyril of Alexandria (died 444), who brought about the fall of another Bishop of Constantinople, Nestorius, at the third General Council, held in Ephesus (431). But at Ephesus there was more at stake than the rivalry of two great sees. Doctrinal issues, quiescent since 381, once more emerged, centring now not on the Trinity but on the Person of Christ. Cyril and Nestorius agreed that Christ was fully God, one of the Trinity, but they diverged in their descriptions of His humanity and in their method of explaining the union of the divine and the human in a single person. They represented different traditions or schools of theology. Nestorius, brought up in the school of Antioch, upheld the integrity of Christ's humanity, but distinguished so emphatically between the humanity and the Godhead that he seemed in danger of ending, not with one person, but with two persons coexisting in the same body. Cyril, the protagonist of the opposite tradition of Alexandria, started from the unity of Christ's person rather than the diversity of His humanity and Godhead, but spoke about Christ's humanity less vividly than the Antiochenes. Either approach, if pressed too far, could lead to heresy, but the Church had need of both in order to form a balanced picture of the whole Christ. It was a tragedy for Christendom that the two schools, instead of balancing one another, entered into conflict.
Nestorius precipitated the controversy by declining to call the Virgin Mary 'Mother of God' (Theotokos). This title was already accepted in popular devotion, but it seemed to Nestorius to imply a confusion of Christ's humanity and His Godhead. Mary, he argued - and here his Antiochene 'separatism' is evident - is only to be called 'Mother of Man' or at the most 'Mother of Christ', since she is mother only of Christ's humanity, not of His divinity. Cyril, supported by the council, answered with the text 'The Word was made flesh' (John i, T4): Mary is God's mother, for 'she bore the Word of God made flesh'.' What Mary bore was not a man loosely united to God, but a single and undivided person, who is God and man at once. The name Theotokos safeguards the unity of Christ's person: to deny her this title is to separate the Incarnate Christ into two, breaking down the bridge between God and humanity and erecting within Christ's person a middle wall of partition. Thus we can see that not only titles of devotion were involved at Ephesus, but the very message of salvation. The same primacy that the word homoousios occupies in the doctrine of the Trinity, the word Theotokos holds in the doctrine of the Incarnation.
Alexandria won another victory at a second council held in Ephesus in 449, but this gathering- so it was felt by a large part of the Christian world - pushed the Alexandrian position too far. Dioscorus of Alexandria, Cyril's successor, insisted that there is in Christ only one nature (physis); the Saviour is from two natures, but after His Incarnation there is only 'one incarnate nature of God the Word'. This is the position commonly termed 'Monophysite'. It is true that Cyril himself had used such language, but Dioscorus omitted the balancing statements that Cyril had made in 433 as a concession to the Antiochenes. To many it seemed that Dioscorus was denying the integrity of Christ's humanity, although this is almost certainly an unjust interpretation of his standpoint.