In 1980, Kirsch and Richard F. Lyon independently invented the first versions of the optical mouse. Kirsch has started several companies. In 1993, he founded the search engine Infoseek, which in 1999 was sold to the Walt Disney Co. He co-founded Frame Technology Corp., bought by Adobe in 1995. In 2002 he was CEO of Propel Software. In 2005 he founded Abaca, which made a spam filter. Sometime before March 2021, Kirsch started M10, which markets blockchains for banks, but the board asked him to step down in the summer of 2021 amid controversy generated by his statements on COVID treatments and vaccines. In May 2021, Kirsch posted an article online questioning COVID-19 vaccines affect on fertility. In October 2021, Kirsch founded Vaccine Safety Research Foundation (VSRF.) Kirsch and his wife, Michele, fund a charitable foundation, which by 2007 had given $75 million to different causes. In 2007, his personal fortune was estimated at $230 million, that same year he was diagnosed with a rare form of cancer and funded research into experimental treatments for it, eventually refocusing the family foundation on medical research.

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