[4] In 1986, Downing was recruited by hematopathologist Coston W. Berard and began working at the St. Jude Children's Research Hospital with Charles J.
[4] On July 15, 2014, Downing became the Chief Executive Officer of St. Jude, making him the sixth person to hold the position.
[5] Downing was one of the inaugural co-editors of the Annual Review of Pathology: Mechanisms of Disease, though he only held the position for the first volume in 2006.
He pioneered the use of genomic profiling in the collection of big data for children suffering from blood cancers, exploring the genetics and genomics underlying acute lymphocytic leukemia, acute myeloblastic leukemia, and other cancers, and using that information to improve patient outcomes.
By 2020, St Jude's had sequenced the exome and transcriptome of another 1,200 patients, identifying a total of 23 types of cancer.