WASHINGTON—The sudden and unexplained departure of Donald Fredrickson as president of the Howard Hughes Medical Institute is due chiefly to conflicts arising from his wife's participation in HHMI activities that exceeded the normal bounds of a spouse's interests, say several longtime friends and colleagues.

According to these associates, Fredrickson's wife has played an active role in certain affairs of the $5 billion organization since Fredrickson became affiliated with the institute in 1983. She has attended numerous meetings of the trustees, was instrumental in the departure of an HHMI employee, pushed through a lavish plan to furnish her husband's offices at the institute's new home in Bethesda, and attended meetings on the Research Scholars Program, an HHMI-supported program that offers medical students a year of research experience in an NIH laboratory.

George Thorn, chairman of the institute and acting chief executive officer, refused to comment about whether Fredrickson's wife, Henrietta, played...

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