FRONTIERS SPARKS OF INNOVATION

Frontiers

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“Providing bright and original minds the opportunity to quickly pursue a new idea does frequently result in unexpected and occasionally fundamental breakthroughs.”
Irwin Jacobs – Chairman, Salk Board of Trustees

The tiny worms from Sreekanth “Shrek” Chalasani‘s laboratory are media darlings. Among other notable media outlets, they’ve made headlines in the Guardian, Scientific American and The New York Times—not to mention the stir they’ve caused in the technical scientific literature.

The worms’ fame stems not from their own merits, but from the fact that they are the first organisms whose brains and behaviors can be controlled using sound waves. The technique for exerting this control, dubbed sonogenetics, was first developed in Chalasani’s laboratory at Salk, and represents a prime example of how supporting a scientist’s creative, if unorthodox, idea can lead to surprising and important innovations.

“Turning specific neurons on and off with sound offers a noninvasive method for studying the brain and opens the door to replace invasive clinical procedures like deep brain stimulation,” says Chalasani, an associate professor in the Molecular Neurobiology Laboratory.

This discovery was made possible by a new kind of support: the Innovation Grants Program, launched in 2006 as the brainchild of Salk Board of Trustees chair and philanthropist Irwin Jacobs. Jacobs and his wife, Joan, committed $8 million to fund out-of-the-box ideas through this program, with the goal of supporting theories based on solid science but with no data yet to suggest success. Such proposals might sound risky in terms of achievement but, if they pan out, have the potential to lead to groundbreaking technologies and discoveries. Too often, scientists’ most creative ideas aren’t explored because they are difficult to fund, but the Innovation Grants Program has turned a number of “wacky” ideas into enviable cutting- edge research programs.

Chalasani’s idea of using ultrasonic waves to manipulate neurons was funded by two Innovation Grants in 2011 and 2015. In September 2015, Chalasani’s team reported early success with the unprecedented approach in Nature Communications, which garnered media attention for his lab.

“Without the Innovation Grants, this project might have never happened. I had no data to even think that sound could be used in this manner,” says Chalasani. “It was a pie-in-the-sky idea in some ways. But the grants helped us to test our idea. More than just funding, the grants gave me the confidence to pursue this novel idea.”

“Turning specific neurons on and off with sound offers a noninvasive method for studying the brain and opens the door to replace invasive clinical procedures, like deep brain stimulation.”Shrek Chalasani, Salk Associate Professor

The grants, Jacobs says, are meant for Salk scientists—all trailblazers in their respective fields—to test a notion or idea so unexpected and new that traditional funding sources, such as government grants, would not typically take on the financial risk. The effort grew, gaining additional supportive donors (the Rose Hills Foundation, James Melcher and April Benasich, Fondation Ipsen, and Elizabeth Keadle) and funding 76 awards averaging $120,000 each to date. Though donors have often supported new scientific research at Salk, the program has helped ensure that bold and creative scientific ideas based on excellent science receive immediate funding.

“This program is intended to provide resources for early, innovative, and often high-risk scientific research, and to do so with minimal delay. We have been very pleased with the originality and success of the funded projects,” says Jacobs. “Providing bright and original minds the opportunity to quickly pursue a new idea does frequently result in unexpected and occasionally fundamental breakthroughs, substantially supporting progress in solving our most pressing science and medical problems.” For example, now Chalasani’s work to expand his technique into mammals has garnered two major grants, one from the Keck Foundation and one from the National Institutes of Health’s BRAIN Initiative, announced in October 2016, to further develop the technology and test the process in mammalian cells, with the hopes of moving to human therapies.

Allowing this unfettered exploration of ideas has resulted in a number of impressive innovations in the last few years alone. Salk Associate Professor Clodagh O’Shea was the recipient of one such grant in August 2013 to explore new technologies related to the complex packaging of DNA and proteins (called chromatin) within a cell’s nucleus. The configuration of chromatin is one that has confounded scientists but holds clues to understanding health and disease. How tucked away and thereby inaccessible genetic material is within chromatin determines whether or not certain genes— such as ones that suppress tumors—are active.

The Innovation Grant helped O’Shea to explore new imaging and sequencing technologies to visualize the structure and function of DNA in time and space—work which has the potential to reveal the structural code that determines if a gene is in an “on” or “off ” state in diseases such as cancer. Aside from better understanding chromatin, O’Shea is also using this knowledge to design synthetic viruses and genetic machines that can infiltrate the nuclei of cancer cells, for example, and selectively destroy tumors.

The work eventually led to O’Shea receiving a 2014 Keck Foundation award in partnership with the University of California, San Diego for $1 million. The next year, she was also one of the recipients of a $120 million, 5-year multi- institute initiative by the NIH to understand the cell’s nucleus.

“The Innovation Grant was like a stepping stone for my lab to get enough data to have a sense that the technology might work,” says O’Shea, holder of Salk’s William Scandling Developmental Chair and an HHMI Faculty Scholar. “The problem with disruptive technologies is that people say it’s never been done before so it won’t work and they won’t fund it. But something like the Innovation Grants allows us to get an inkling that an idea could be possible and gather data for a proof-of-principle to get more funding to then take the research further.”

“The innovation grant was like a stepping stone for my lab to get enough data to have a sense that the technology might work.”Clodagh O’Shea, Salk Associate Professor

In another example of cutting-edge science finding traction through Innovation Grants, Salk Professor Satchidananda Panda received support to examine how eating and lifestyle activities affect daily biological cycles (circadian rhythms) and, by extension, health and illness. His Innovation Grant backed a study into the ebb and flow of genes tied to circadian patterns in baboons in Kenya. Through the research, which has been extended with additional funding from the U.S. Department of Defense, Panda aims to chart daytime and nighttime patterns of gene activity and reveal cellular “switches” that could help reset or control circadian rhythms.

Panda’s line of research could have vast implications for treating jet lag, sleep disorders, shift work and overall health. For example, he has published data demonstrating that mice which eat within a set amount of time (12 hours) resulted in slimmer, healthier mice than those who ate the same number of calories in a larger window of time, indicating that when one eats in relation to circadian rhythms may be as important as what one eats. Additionally, his research has uncovered that circadian rhythms even mediate the immune system, suggesting that genes and molecules involved in the circadian clock could be drug targets for conditions linked to inflammation, infections or cancer.

“The Innovation Grant’s support was critical to explore this novel idea which now has been gaining traction in the field and in the press,” says Panda. “It appears that circadian rhythms can have profound effects on eating disorders, diabetes, obesity and other health ailments.”

“It appears that circadian rhythms can have profound effects on eating disorders, diabetes, obesity and other health ailments.”Satchidananda Panda, Salk Professor

The list of innovations since the program’s inception continues across labs. Of the awards granted, about 30 to 50 percent of the projects have successful results—an exceedingly promising success rate for ideas that may originally be viewed as far-fetched. “Support like the Innovation Grants is one of the few ways big-risk—and big- reward—scientific endeavors happen,” says Salk Research Development Director Michael Nunn, who oversees the Innovation Grants process. “The program is one of the things that keeps Salk at the cutting edge.”

The Innovation Grants aren’t just for early career scientists. This support allowed Salk Professor Tony Hunter to develop new tools to study the role of a little understood chemical process (histidine phosphorylation) and Salk Professor Vicki Lundblad to dig into what happens at the ends of chromosomes, called telomeres, which are tied to a cell’s health and an organism’s lifespan. Both scientists received additional support from federal grants to continue their research. In another success story, Salk Professors Martyn Goulding and Ed Callaway made dramatic inroads in tracing neural circuits and optogenetics—the more mature cousin of sonogenetics.

“We have been able to push the boundaries of neuroscience thanks to the Innovation Grants,” says John Reynolds, a Salk professor who received Innovation Grants along with Salk Professor Kuo-Fen Lee to develop a new mammal research model based on the marmoset to better understand gene activity, neurobiology and vision. After initial promising results, Lee and Reynolds are exploring other avenues of funding to continue research in this area. “We are optimistic about receiving additional support to explore new aspects of neurodegenerative disease, in particular Alzheimer’s, in the marmoset model,” says Lee.

“Ever since Jonas Salk brought the first scientists to La Jolla, the Institute has been a beacon for scientific excellence, interdisciplinary collaboration and fearlessness in intellectual exploration,” says Salk President Elizabeth Blackburn. “By developing programs like the Innovation Grants and others to offer unfettered support for big-thinking and brilliant science, we are able to ensure an emergence of the most creative science discoveries.”

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