The couple pledged the money as the next big investment by their philanthropic company, the Chan Zuckerberg Initiative, which is also focused on education, poverty, and equality.
Speaking through tears at a San Francisco event to announce the initiative, Ms Chan said she hoped to spare parents the pain she had seen while delivering difficult news as a pediatrician. "In those moments and in many others we're at the limit of what we understand about the human body and disease, the science behind medicine, the limit of our ability to alleviate suffering. We want to push back that boundary," she said.
Bill Gates, the chairman of Microsoft, San Francisco Mayor Ed Lee and California Lieutenant Governor Gavin Newsom also attented the event.
The first wave of cash will be a $600m investment in a new research centre called Biohub, which is a partnership with Stanford, Berkeley, and the University of California, San Francisco and is tasked with finding new ways to fight disease.
Mr Zuckerberg said science and the medical community have made rapid advancements over the past 50 years, including eradicating smallpox and nearly eliminating polio. "Today, just four kinds of diseases cause the majority of deaths," he added in a posting on his Facebook page, citing cancer, heart disease, infectious diseases and neurological diseases. "We can make progress on all of them with the right technology."
In December last year, Mr Zuckerberg said he will give 99 per cent of his Facebook shares away in his lifetime. He made the promise in an open letter to his newborn daughter, Max, on Facebook. He said he would dedicate 99 per cent of his shares in Facebook to the four missions: personalised learning, curing disease, connecting people and building strong communities.
The Facebook founder is worth $56bn, thanks to shares in his own company. In April, he seized the opportunity to propose a new class of nonvoting stock to make sure that he retains the major control of his company.
Earlier this week, Microsoft has pledged to "solve" cancer in the next 10 years.
The company is working at treating the disease like a computer virus that invades and corrupts the body’s cells.
Additional reporting by Reuters
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