The Mello family moved to Falls Church in northern Virginia so that James could take a position with the United States Geological Survey (USGS) in Washington, DC.

[2] After a brief stay in Falls Church, the family moved to Fairfax, Virginia, when James Mello switched from the USGS to a position as assistant director at the Smithsonian Museum of Natural History.

At a time when young Mello was not performing so well in school, these daily discussions helped to build his confidence and self-esteem.

[2] After receiving his high school diploma, Mello attended Brown University as a biochemistry and molecular biology major.

Kenneth Miller, his cell biology instructor, recounted that although he did not receive the "best grades of the class," he was intensely curious and thus a "real pain in the ass.

[2] Mello attended the University of Colorado, Boulder for graduate studies in molecular, cellular and developmental biology with David Hirsh.

After Hirsh decided to take a position in industry, Mello moved to Harvard University where he could continue his research with Dan Stinchcomb.

[2] In 2006, Mello and Fire received the Nobel Prize for work that began in 1998, when Mello and Fire along with their colleagues (SiQun Xu, Mary Montgomery, Stephen Kostas, and Sam Driver) published a paper [4] in the journal Nature detailing how tiny snippets of RNA fool the cell into destroying the gene's messenger RNA (mRNA) before it can produce a protein - effectively shutting specific genes down.

In the annual Howard Hughes Medical Institute Scientific Meeting held on November 13, 2006 in Ashburn, Virginia, Mello recounted the phone call that he received announcing that he had won the prize.

[2] He believes that "The science vs. religion debate is over" and that it is possible to "unite rationality and spirituality in a worldview that celebrates the mysteries of existence and inspires each human being to achieve a higher purpose in life"[6] In his October 2015 acceptance speech for a China Friendship Award from Premier Li Keqiang Mello said,[7] Science is a unifier.

Science counteracts these forces, it is a worldwide enterprise that unifies us and brings us together to solve problems and to understand our place in the world.