At the end of every year, Bill Gates questions himself. It’s part of a long-standing tradition, one upheld by many of us, as we set resolutions and broader themes for the year ahead.

Over the years Gates’s questions have changed drastically, he writes in a just-released year-end letter. In his 20s, it was just one, really: Is Microsoft software making the personal-computing dream come true?

Now 63, he is steering billions of dollars in philanthropy to meet ambitious health and development goals, rather than focusing on software, and probing how well the foundation has done every year. Broader life questions are cropping up, too, he writes. “Did I devote enough time to my family? Did I learn enough new things? Did I develop new friendships and deepen old ones?,” he wonders. There’s also a bonus question, courtesy of Warren Buffett: “Do the people you care about love you back?”

“These would have been laughable to me when I was 25, but as I get older, they are much more meaningful,” Gates writes.

It’s not just his own aging that’s causing the shift, Gates believes—there’s global transition in the way we think about well-being. “For most of human history, we have been focused on living longer by fighting disease and trying to grow enough food for everyone,” he writes. Now that life spans have increased drastically, the focus is on improving the quality of life. ”I think this will be the thrust of many big breakthroughs of the future,” Gates predicts.

Here’s what Gates says went well and what didn’t in the areas he works in:

Advances in Alzheimer’s research

Researchers have focused on a new set of theories about Alzheimer’s disease in 2018. One theory suggests brain cells break down because their energy producers wear out, another that brain cells break down because some part of the immune system is overactivated and attacks them. “This is a great example of how improving our understanding of biology will reduce both medical costs and human suffering,” Gates writes. Another positive trend in 2018 is that researchers are getting more and better access to data on Alzheimer’s sufferers.

Recruiting patients for clinical trials remains a key obstacle, though. It can take years to enroll enough people in trials because there isn’t a “simple and reliable diagnostic” for Alzheimer’s, Gates writes, making it hard to find eligible people at early stages of the disease.

Eradicating Polio remains elusive

“I thought we would be closer to eradicating polio today than we are,” Gates writes. “I underestimated how hard it would be to vaccinate children in places where there’s political violence and war.” In 2018, the number of cases of wild poliovirus increased to almost 30, all of which were in Afghanistan and Pakistan (the only two countries that have never been free of polio.)

But there are advances. New innovation has made it possible to test sewage samples to track the virus and find the source before an outbreak starts. And there are new ways to work in war zones, evidenced by outbreaks stopping in Syria and Somalia. Finally, Gates is hopeful about a new oral vaccine that is being tested in Belgium and Panama that could be in use as soon as 2020. “Despite all the challenges, I am still optimistic that we can eradicate polio soon,” he writes.

Reviving nuclear energy

Global emissions of greenhouse gases increased again in 2018. Gates doesn’t believe solar and wind energy are enough, nor that batteries will be sufficiently cheap enough in the near future to store enough energy when the sun isn’t shining or the wind blowing. Gates’s Breakthrough Energy Ventures, a clean-energy investment fund, is funding a variety of companies tackling climate change, he still thinks there needs to be even more radical investments and solutions.

Gates says he will spend 2019 urging the US to regain its leading role in nuclear power research. “Nuclear is ideal for dealing with climate change, because it is the only carbon-free, scalable energy source that’s available 24 hours a day,” he writes. Plans to build a pilot project in China for TerraPower, a Gates-backed company founded 10 years ago that says it uses safer reactors, have been hampered by changes in US policy. To build in the US, there would need to be new funding and updated regulations, which Gates will lobby for.

Failure to prevent the next epidemic

2018 marked the 100-year anniversary of the Spanish flu that killed more than 50 million people, but it didn’t spark the discussion about the disease that Gates hoped. We are not prepared for the another epidemic, he writes. “If anything is going to kill tens of millions of people in a short time, it will probably be a global epidemic,” he warns. “And the disease would most likely be a form of the flu.”

Today, a flu like the Spanish flu would kill nearly 33 million people in just six months, he writes.

This year little progress was made on epidemic preparedness, including governments working together on quarantines, medicinal supply chains, or military use. However, there is scientific progress on a vaccine that would protect people from every strain of the flu, Gates writes. This would be most effective for people who have never been exposed to the flu, such as the very young. For anyone who has ever had the flu, the challenges are still enormous.

A public debate on gene editing

A group of Chinese scientists said in November they had helped to create two genetically-edited babies. Their announcement was condemned by other doctors and scientists, who said they had taken gene editing too far by conducting the experiment directly on human beings. As Chinese scientists explained in a letter denouncing the experiment, “such irreversible alterations on human genes will inevitably go into the human gene pool.”

Gates also criticizes the scientists, but argues there could be a positive side effect of their experiment: more people talking and learning about gene editing. This topic should be part of a great public debate, like artificial intelligence, he writes. For those who want a deep dive, Gates recommends The Gene by Siddhartha Mukherjee. (Find it here in the complete list of every book Gates has recommended since January 2010.)

Gates’s 2019 resolution

“I am committing to learn and think about two key areas where technology has the potential to make an enormous impact on the quality of our lives, but also raises complex ethical and social considerations,” he writes. They are the “balance between privacy and innovation,” and “the use of technology in education.”