"So, it's discouraging to hear that kind of talk", she added.
The letter closes by inviting people to the couple their own toughest question.
But the Gateses also say they are looking for ways to expand their work in the United States, particularly to help people move up the economic ladder.
"Although we have had some success", Melinda Gates wrote, " I think it would be hard to argue at this point that we made the world focus too much on health, education and poverty".
Believed to be the largest in the world, the foundation gave away more than $US41 billion ($52 billion) from its inception in 2000 through the end of 2016, now spending $US4 billion to $US5 billion a year to combat malaria, reduce poverty and improve education. "And it's not fair that our wealth opens doors that are closed to most people", Melinda said in response to a question on whether it is fair they have so much influence. "Private companies, governments, non-governmental organisations, academia, and other stakeholders need to work together to create sustainable solutions", said Thierry Diagana, Head of NITD, commenting on the partnership.
Bill and Melinda Gates discussed their optimism about the world's progress, their philanthropic work, as well as how President Donald Trump's policies are affecting their work.
In terms of education, the Gates Foundation primarily targets high school-related endeavors, and also supports early learning and postsecondary education. And people on both sides of the political aisle have questioned the Gates-backed Common Core State Standards.
"It's authentic to take on tough questions, and not use just your typical P.R. format", said Bill George, the former CEO of Medtronic and a senior fellow at Harvard Business School, applauding the approach. The question is how best to do it. "That debate is healthy", he said. "Once you've taken care of yourself and your children, the best use of extra wealth is to give it back to society", he said. "This can't be a one-and-done thing".
"If you appear to be more transparent and more involved and more of a listener, people are going to raise their expectations of you", Argenti said.
The Gates' added that is one reason why they started their philanthropic foundation, which aims to steer funding toward ideas and programs that can alleviate poverty and inequality around the world. She said the Trump administration's decision a year ago to expand a ban prohibiting USA aid to any health organisations that provide or discuss abortion in family planning had caused "chaos" in the field - forcing them to stall their work as they figured out how to adhere to the rules. "The world is not a safer place when more people are sick or hungry".
In the interview, he reiterated that view, saying the Gates Foundation is "working extra hard to articulate the benefits - even in a USA -centric framework - of less need to go out with hard power", or a show of coercive or military force.
As one of the founders of the modern tech industry, Bill Gates is often looked to for technical answers.
The Gates and their foundation have opened up at times in the past about when they've fallen short.