Investing in People: The Power and Promise of High-Risk Science

Parker Bridge Fellow Ansuman Satpathy, MD, PhD, on the importance of early career support for big ideas in cancer research

There’s a Ray Charles song called “Them That Got” in which the singer observes, “If you gotta have somethin’ before you can get somethin’, how you get your first is still a mystery to me.” It’s a lyric most early career scientists can relate to as they navigate which comes first: experience or opportunity? Before running a lab, proving ideas can get funded, or establishing a track record of independent science, any young researcher with a potentially game-changing approach has to find someone to believe in them enough to commit to their work.

That commitment means funding, of course, but it’s about more than just the money. It’s also about finding the support of people who believe in them personally and who can surround them with the right mentors and collaborators – people who can help them turn their big ideas into reality as they try to solve the toughest problems in their field.

Enter Ansuman Satpathy, MD, PhD, a Parker Bridge Fellow and an Assistant Professor in the Department of Pathology at Stanford University School of Medicine. Trained as an immunologist and focusing his research on genomics and computational biology, he found himself with the chance to work in cancer immunotherapy in 2017. Howard Y. Chang, MD, PhD, Satpathy’s mentor at Stanford and a PICI investigator, encouraged him to apply for the fellowship, which is a program for senior postdoctoral investigators who want to answer the most critical questions in cancer immunotherapy as they transition to faculty positions. Though he’d never worked on cancer immunotherapy directly, Satpathy says he was intrigued, and he jumped at the chance to apply everything he’d worked on so far and make his own mark on the field.

“It’s always about the next big idea, not about the next thing you think someone might be willing to fund.”

“As I started to learn what questions the leaders in the field were asking, what ideas they were thinking about, and how they were approaching problems, I realized I had my own set of tools that I could bring to bear,” Satpathy said.

Satpathy’s initial work included first authorship on two particularly notable pieces of research that changed the way the field understood the mechanism of action of PD-1 inhibitors – the most common immunotherapy used in cancer today – and their relationship to T cells. A study published in Nature Medicine showed anti-PD-1 therapy doesn’t reinvigorate pre-existing T cells, but rather recruits new T cell clones. Another study in Nature Biotechnology found exhausted T cells have a distinct molecular state, which helps explain what stops them from being turned on after PD-1 therapy. These are critical problems to solve, and they have the tantalizing promise of helping more patients respond to game-changing checkpoint inhibitor therapy ­– and unlocking an even broader ability to deliver effective treatments for cancer patients.

This research was guided collaboratively by thought leaders in the field, all working together under the PICI umbrella. It’s that support and ability to share big ideas that Satpathy says is so unique about the PICI model and how it has enabled his career.

“The best part of this isn’t the financial support, it’s the small group of really excellent scientific leaders and industry leaders that are working as part of a community,” Satpathy said.

The work helped Satpathy establish his own lab, and his research group recently published its first study. The paper, published in Cell, detailed the presence of CD-19 on a rare cell type in the brain, shedding new light on why existing CAR T cell therapies may cause neurotoxicity in some patients. Just like the work on PD-1 inhibitors, this research answers a critical question about a game-changing therapy. It also helps to lay the foundation for future work to find markers specifically expressed in tumors and not healthy cells. The idea holds enormous promise, as it would allow researchers to pick more effective targets with a better ability to understand potential effects.

Someday, it may be easy to draw a straight line from this research to the development of better therapies for cancer patients. But for the researchers themselves, the science never feels like a direct course. Instead, it falls into the category of what is often called “high-risk, high reward” science. It’s a common phrase, and it’s the kind of buzzwordy board room talk than can excite the right audience. But there’s a part of the term that often goes unspoken: failure. With high-risk science, there is also a higher chance of hitting a few dead ends along the way. Satpathy says the most effective support for researchers is focused on people and big ideas rather than risk ratios.

“Supporting high-risk science means supporting the fact that things will fail – and when they fail, a researcher has the support and the freedom to pursue the next idea that comes from that failure,” Satpathy said. “That intellectual freedom changes the way you think. It’s always about the next big idea, not about the next thing you think someone might be willing to fund.”

Satpathy also notes this is where the culture of collaboration among the other PICI researchers plays a critical role. As new ideas form, top minds from industry and academia become a sounding board for how best to pursue them.

“Maybe someone else has tried something like this, or maybe there is other data out there that doesn’t fit with yours. In the end, you prune your ideas down and agree to work together to pursue the best ones,” Satpathy said.

Satpathy says that culture – the ability to grow close enough with people outside your organization to share your craziest ideas with them – is unique to PICI, in his experience. And he says his exposure to that, along with the early career support he received from PICI and from the Cancer Research Institute (CRI), a PICI partner, are responsible for getting him to where he is now.

“Other sources of funding take longer and are exclusively focused on projects that have a high probability of success,” Satpathy said. “It’s not overstating it to say that if PICI and CRI had not funded me as a young researcher and started my independent career, I wouldn’t be focusing on what I am today.”