When Mark Zuckerberg announced in a letter to his newborn daughter that he and his wife, Dr. Priscilla Chan, would use 99 percent of their Facebook wealth for philanthropy, he wrote of funding medical research that could lead to “a world without suffering from disease.”

Many researchers were predictably thrilled that one of the most famous entrepreneurs in the world is making a public commitment to medicine. But others sounded a note of caution.

“I think it makes people feel good, and has some value there. Certainly I think we’re glad that people are giving this money rather than not giving,” Maryann Feldman, a University of North Carolina economist who has researched philanthropic organizations, said in an interview. “But then the question remains: If they paid it in taxes, then in a democracy, we would decide how it would be spent. That’s sort of missing in this model.”

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Dr. Eric Lander, one of the top researchers involved with the Human Genome Project and the co-chair of President Obama’s Council of Advisors on Science and Technology, said the decision by Zuckerberg and Chan could set “a model for their generation.”

At the same time, he advised thoughtfulness and prudence. A high-profile announcement of such a huge sum is also sure to attract all sorts of suitors.

“It’s up to them how to process all of the ideas that may come forward. I think the right solution is to start thoughtfully and slowly,” Lander said. “They’re in their early 30s. Their lifetime is a long time. I think they have time to get it right.”

Moonshot miss?

Zuckerberg and Chan pledged to invest over their lifetime 99 percent of their Facebook shares, equal to $45 billion in today’s dollars. Rather than spending the money through a charity, they’ll be setting up a limited liability company, which will allow them to engage in activities traditionally off-limits to nonprofits, such as making a profit, and spending a lot of money on lobbying.

Some analysts worry that model will be less transparent and harder to hold accountable.

And then there’s the bottom line: How much could they actually do for health?

For starters, the size of the investment into medical research isn’t clear: Zuckerberg also named Internet access, education, and community building as some of the couple’s other goals. They are planning to sell or give no more than $1 billion in shares each year over the next three years to the Initiative, with future amounts to be determined.

Moonshot goals can be appealing, but many experts in the field say less ambitious, more incremental advancements are what really make a tangible improvement to people’s lives.

“The answers and the solutions come in very small packets, and that’s just the nature of science, that it’s more incremental than the concept of a major breakthrough,” Jo Handelsman, the associate director for science at the White House Office of Science and Technology Policy, said in a recent interview with STAT.

Philanthropy is no guarantee of medical breakthrough, and there are pitfalls.

Zuckerberg has experienced some of these obstacles before. In 2010, he made headlines with a $100 million initiative to improve education in Newark — and again four years later as journalists and analysts questioned the effectiveness of his donation. In a November 2015 Facebook post, Zuckerberg wrote that he had learned many lessons from the Newark initiative, including the importance of engaging the community and thinking in the long term.

These challenges are not unique to young philanthropists. The Bill and Melinda Gates Foundation, which in 2014 made $1.1 billion in grants toward global health projects, has also struggled to balance long-term planning with short-term impact. Gates himself has acknowledged that it will take longer than anticipated for some of its projects to come to fruition.

A foundation official also told SciDev.Net in January that, while individual vaccine-related projects have been successful, the foundation hasn’t done enough to improve the infrastructure used to transport those vaccines to people.

Chan and Zuckerberg have already made multiple contributions toward scientific and medical research. In 2012, they established the “Breakthrough Prizes,” which are annual $3 million prizes for physics, life sciences, and mathematics. At the beginning of 2014, they donated $5 million to the Ravenswood Family Health Center, located in East Palo Alto. Later that year, they pitched in on the fight against Ebola, donating $25 million to the Centers for Disease Control Foundation.

And this past February, they gave $75 million to the San Francisco General Hospital Foundation as part of a fundraising campaign; their gift allowed the hospital to build a “hybrid operating room” equipped with robotic arms to assist surgeons during procedures, said Amanda Heier, CEO of the foundation.

No substitute for public investments

Those involved in medical research will be watching closely to see how Zuckerberg has learned from that history and how he and Chan navigate their new endeavor.

Francis Collins, director of the National Institutes of Health, said he looked forward to talking with Zuckerberg and Chan about their plans, saying that he was “thrilled” by the announcement. But he suggested that such efforts shouldn’t be used as a reason to scale back on government funding.

“Most philanthropic efforts are rather targeted toward specific diseases that the philanthropist is interested in. It’s unusual for philanthropy to support a lot of basic science, and yet the future of everything we hope to see happen in medical research depends upon a vigorous agenda in the basic arena,” Collins said. “That’s where the government is really very important in the effort.”

Lander agreed that one depended on the other. The NIH’s annual budget is $30 billion; Zuckerberg and Chan are, at least at the onset, committing to $1 billion a year at most for all of their philanthropic interests, only one of which is medical research.

“No matter how large the philanthropic resources are, they don’t come close to what we as a nation spend on research, nor should it or could it,” Lander said. “It cannot quantitatively substitute for public investment.”

“What they can do is allow scientists to take bold risks, to work in different ways, to experiment and pilot different approaches that don’t fit in” with the public sector, he continued. “It gives them a chance to pioneer new approaches.”

David Nather contributed to this report.

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