In 1986, Downing was recruited by hematopathologist Coston W. Berard and began working at the St. Jude Children's Research Hospital with Charles J. Sherr.[3]
He became Chairman of the Department of Pathology and Laboratory Medicine in 1997 and Deputy Director in 2011.[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 has studied the molecular basis underlying pediatric leukemia, leading to significant discoveries in hematopathology and molecular biology. 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.[4][7]
In 2010, Downing launched the Pediatric Cancer Genome Project in an effort to determine the genetic lesions that underlie childhood cancers. By 2013, the project had sequenced the genomes of over 700 pediatric cancer patients and 21 different types of cancer.[8][3] Next, the Clinical Genomics Project focused on using the PCGP findings to improve diagnostic and clinical treatment for St. Jude patients in "Phase II” of the project. By 2020, St Jude's had sequenced the exome and transcriptome of another 1,200 patients, identifying a total of 23 types of cancer. Among their discoveries were genomic differences between cancers in children and adults, and the finding that about 10% of children with cancer display mutations in known cancer-predisposition genes.[9]
In 2018, Downing led St. Jude Children’s Research Hospital in partnering with the World Health Organization to create the first WHO Collaborating Centre for Childhood Cancer and start a Global Initiative for Childhood Cancer, working with over 50 governments worldwide. In December 2021, they announced the Global Platform for Access to Childhood Cancer Medicines, to increase access to cancer medicines for the nearly 90% of children with cancer who live in low and middle income countries (LMICs). The project will provide medicines to countries at no cost during the pilot phase.[10][11]
^"Annual Review of Pathology: Mechanisms of Disease. Volume 1: 2006. Edited by Abul K Abbas, James R Downing, and , Vinay Kumar. Palo Alto (California): Annual Reviews. $55.00. Xii + 552 p; ill.; subject index. ISBN: 0‐8243‐4301‐8. 2006". The Quarterly Review of Biology. 81 (3): 314. 2006. doi:10.1086/509485.