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Rh daughter-school of Antioch was at Edessa, where a line of Syriac Fathers flourished—St. Ephrem (Afrēm, † 373), Aphraates (Afrahat, † end of 4th century), Rabulas (Rabūla, † 435), Isaac the Great († c. 459), &c. But the Antiochene school, in spite of the fame of the Catholic Doctors who had belonged to it, was as suspect of unorthodoxy as its rival in Egypt. Theodore of Mopsuestia was a Nestorian, Theodoret of Cyrus was an opponent of St. Cyril of Alexandria, and the school in general shared at least some of the Nestorian ill-fame that, after the Council of Ephesus, attached itself to Edessa.

It was about the See of Antioch that the greatest schism of the first four centuries took place (Meletius, p. 90). There is a very remarkable likeness between the history of the two great Eastern Patriarchates. Each of the Macedonian cities, Alexandria and Antioch, remained, after Alexander's Empire had broken up ( 323), an outpost of Greek civilization in the midst of barbarians. Rome had swallowed up the Ptolemies, ( 30) and the Seleucids ( 64), but still these two cities remained Greek. The citizens of both spoke Greek, while all around the old barbarian populations of the lands (Egyptians and Syrians) clung to their own languages and customs, and hated the Roman Emperor as much as they had hated Alexander's generals. Both populations found in Church matters an outlet for their national and anti-imperial feeling. And so just as the greatness of the Church of Alexandria came to an end through the schism of the Egyptians, so did Antioch fall when her Syrians adopted heresies that had, at any rate, the advantage of not being Cæsar's religion. Lastly Islam poured over Antioch too.

In Syria both the opposite heresies, Nestorianism and Monophysism, helped to ruin the Church of Antioch. After the Council of Ephesus (431) nearly the whole of the eastern part of the patriarchate remained Nestorian. The writings of Theodore of Mopsuestia had spread this heresy all around Edessa and Nisibis, the school of Edessa was its chief centre,