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When Curiosity Leads to Transformative Basic Science Discoveries [Alliance blog post]

On a clear February day in San Francisco, the University of California, Berkeley, and the Science Philanthropy Alliance cohosted an event for funders interested in basic science. Carol Christ, the university’s chancellor, welcomed attendees to the event, noting the importance of basic science.

One of the highlights of the event was a panel that the event emcee, NPR science correspondent Joe Palca, moderated featuring three brilliant scientists, all faculty members at UC Berkeley. Jennifer Doudna (of CRISPR fame), Saul Perlmutter (2011 Nobel laureate), and Randy Schekman (2013 Nobel laureate) talked about the path to their transformative discoveries and discussed the importance of basic science.

Jennifer Doudna’s research focuses on the fundamental questions of how cells control the flow of genetic information using molecules called RNA to do so. She described her groundbreaking work on CRISPR CAS-9 as serendipitous, starting in 2006 with an offer to help a colleague, geo-micro-biologist Jill Banfield, who was exploring how bacteria respond to viruses.

“Jill had a hypothesis she wanted to test, so we got together, and this morphed into our investigation of ‘clustered regularly interspaced short palindromic repeats,’ also known as CRISPR. The work on this bacterial immune system then led to my work with Emmanuelle Charpentier that uncovered the activity of a protein called CAS-9, which uses RNA molecules derived from viruses to help cells find and destroy viral DNA.”

“As we did the biochemical experiments, we realized that what we were doing with CAS-9 could be used more broadly. Scientists could program this protein to find and cut any segment of DNA, like having magical shears that go into a cell, find a place in DNA to make a cut, and then make a repair, in the process changing the genetic information,” said Doudna. “It all started with curiosity and became something very different.”

left to right: National Public Radio’s Joe Palca and University of California, Berkeley scientists Randy Schekman, Saul Perlmutter, and Jennifer Doudna

Saul Perlmutter agreed that curiosity was the driving force for his work. As an astrophysicist, he is fascinated by fundamental questions. His work led him to the discovery of the accelerating expansion of the universe, which earned him the 2011 Nobel Prize, which he shares with Brian Schmidt and Adam Riess. Perlmutter now wants to know why the universe’s expansion is accelerating. Although intellectually fascinating, the information that is accessible right now appears useless for more practical purposes, just as the theory of general relativity once did. Yet general relativity went on to be critical to global positioning system (GPS) technology. “So far, we have learned something key to our understanding of the universe we live in—and that by itself would be enough for one discovery to do for us. But who knows? It could also transform our capabilities. You need first to understand how something works before you can see if it could be useful elsewhere,” said Perlmutter.

Another Nobelist, molecular and cell biologist Randy Schekman, was enticed away from medical school plans his freshman year in college by his interest in how cells work, grow, and divide.

“My interest was in how cells manufacture protein molecules. Thirty percent of the proteins made by the 23,000 genes in our body get shipped out of the cell perimeter. Scientists in the ‘60s and ‘70s had observed that proteins are shipped out of the cell perimeter, but how this worked was a mystery. So when I arrived at Berkeley in 1976, my approach was to devise a genetic approach to examine how this worked in a similar, simple organism—baker’s yeast—which turned out to be similar to human cells,” explained Schekman.

“I found out later that Chiron, a local biotech company, used yeast to express proteins in order to make insulin. This was an unexpected result. I had not thought of my research turning into technology to produce insulin. But that’s what happens with basic science. There will be entrepreneurial people out there who will use basic science discoveries in ways the scientist never dreamt of,” he said.

Palca noted that discovery science is not a linear process. “What happens when you have a great idea but you’re stuck?” he asked. Schekman noted that scientists have to be willing to take a gamble and to take risks. Those who have the courage of their convictions will eventually find a way to take a problem and turn it around.

“I started with an approach in an area in which I had no experience, but I was willing to pursue it and I had great graduate students,” said Schekman. “When I peered into the microscope and saw the dramatic effect of mutation on yeast cells—the cell had exploded, with vesicles all over the place—I knew I had my life’s work ahead of me.”

Robert Tjian, professor of biochemistry and molecular biology at UC Berkeley, noted that the risky nature of basic science is why the Science Philanthropy Alliance was founded. Tjian was the president of the Howard Hughes Medical Institute and worked with five other foundations to start the Alliance in 2012. “Nonprofits and philanthropists have the capacity to take higher risks, to support the kinds of research that the NIH won’t fund,” he said.

Palca also asked the scientists about the right conditions for basic science discoveries. Schekman thought that an individual scientists’ instinct drives creativity, though teams are required to do the work. Perlmutter noted that in astrophysics, teams are critical. “All the discoveries I’ve been engaged in have been made by 20- to 30-person teams. I just led those activities,” he said.

For Doudna, it was a collaboration of herself, two students, and Emmanuelle Charpentier’s small team. The work has now expanded to much larger teams of 20 to 30 people.

At the end of the day, Frances Hellman, the dean of mathematical and physical sciences at UC Berkeley, said, “Basic science is a process with twists, turns, dead ends, and new ideas. Without it there are no translations or cures. With it we have lasers, GPS, CRISPR, and a better understanding of the universe.”

Michael Botchan, the dean of biological sciences at UC Berkeley, agreed, “We don’t always know where basic science will take us, or even how to define the term. However, at its heart, the endeavor is driven by curiosity about core questions where deep general principles are at stake. Basic research leads in unanticipated ways to practical translation but also provides a deeper understanding of what it means to be human.”