How Early BBRF Grants Helped Place Two Young Investigators on the Path to Major Career Success
"A research career is all about a path. And for me, the path really started with BBRF.”
So says Dr. Carolyn Rodriguez, now of Stanford University, whose undergraduate degree in computer science, Ph.D. in neuroscience and genetics, and M.D. degree—all earned at Harvard—put her on a trajectory to launch a career as a psychiatrist, neuroscientist, and clinical researcher.
Back in 2008, when she began putting together her application for a BBRF Young Investigator grant, Dr. Rodriguez was one of thousands of young people in the U.S. and around the world with an excellent academic background and great potential who nevertheless needed to secure financial support in order to set up a lab and get her first research project off the ground.
As she came to the end of the fellowship that followed her academic training, she recalls that “the BBRF grant was the very first grant in the psychiatry/mental illness field that I applied for. It was really where I got my start. I had come out of medical residency and I wanted to have a career in mental health research.”
Dr. Rodriguez succeeded on her first try in obtaining a highly sought-after BBRF grant—she was named a Young Investigator in 2009. “And having that money allowed me to do my very first study.” It focused on a drug that was thought to alter the activity of NMDA receptors, docking ports on nerve cells for the neurotransmitter glutamate. Glutamate is the main excitatory chemical messenger neurons use to communicate.
She wanted to test the idea that an excess of glutamate was responsible, at least in part, for some of the symptoms of obsessive-compulsive disorder (OCD). Minocycline was an antibiotic that had been reported to modulate glutamate’s effects in the brain. It seemed a good place to start: it was inexpensive, already FDA-approved for use in adults and children, and had minimal side effects.
The 2009 Young Investigator-supported study enabled Dr. Rodriguez to gather preliminary data that then persuaded the National Institutes of Health to extend her project with a K23 award, which, like the Young Investigator grant, seeks to sustain promising research careers in their early stages. “That K23 would not have been possible without having the pilot data directly generated from the BBRF Young Investigator grant,” Dr. Rodriguez says.
In the K23 extension of that work, she also studied ketamine, designed as a powerful anesthetic but discovered in the 1990s to have, at very low “subanesthetic” doses, a remarkably rapid anti-depressant effect in severely depressed people who did not respond to existing antidepressant treatments. (That discovery was made by Drs. Dennis Charney and John Krystal, both BBRF Scientific Council members and past grant recipients—work for which they were awarded the BBRF’s Colvin Prize in 2019. A chemical derivative of ketamine called esketamine was approved by the FDA in 2019 for refractory depression, making it the first rapid-acting antidepressant to reach the market.)
Research is all about surprises, and Dr. Rodriguez had a big one when she extended the work on that first BBRF grant. In her government-supported K23 grant, she was able “to do the first randomized study [in people] of ketamine in OCD, and we got fantastic results.”
Carolyn Rodriguez benefitted from the multiplying power of BBRF grants not once, but twice. In 2014 she applied for and received a second BBRF Young Investigator award. “This grant enabled me to look at another molecule that modulates glutamate, called rapastinel. BBRF supplied the means that enabled us to do a small pilot study in OCD.”
As she noted in a letter to the American Journal of Psychiatry, in a sample of 7 OCD patients, she and her team “found rapastinel decreased symptoms of OCD, anxiety, and depression within hours, and was well tolerated. It did not produce the side effects seen with ketamine in OCD.” The helpful effects of the drug were not long-lasting—gone within a week in the 2016 pilot study— but were a hopeful step forward.
Being in position to do this small but consequential study on rapastinel was something Dr. Rodriguez attributes “directly” to BBRF support. Her second grant therefore, like the first, “provided a chance to generate exciting data that could then be funded on a larger scale by the NIH.” The point, she says, is that “the NIH isn’t going to give money for a project like ours that didn’t already have existing pilot data. That’s where BBRF grants bridge the gap.” In this and so many other cases, early-career BBRF grants have a “multiplier effect.” A start-up grant provides the basis for much larger, steady federal support which often endures for an entire career.
In 2017, Dr. Rodriguez received her first “career” grant from the NIH—a grant called an R01—which recognizes that an investigator has achieved results of sufficient interest and importance to justify long-term federal support. Indeed, that R01 grant is one of the main financial pillars sustaining the now bustling Rodriguez lab at Stanford.
“We are investigating the rapid therapeutic action of ketamine at the molecular, circuit, and network level in adults with OCD,” she says.
Dr. Rodriguez’s vision is to investigate the brain basis of intrusive thoughts and to use that knowledge to develop rapidacting treatments for such disorders as OCD and PTSD. Her lab’s studies focus on targeted therapies in the glutamate and opioid pathways, extinction-based psychotherapy (used for example to control fear in PTSD), and non-invasive brain stimulation interventions.
Upon accepting her honorable mention for the Klerman Prize for Exceptional Clinical Research in 2017, Dr. Rodriguez shared these thoughts about BBRF: “I have seen first-hand how the Brain and Behavior Research Foundation has accelerated the pace of psychiatric research by fostering innovative research. The Young Investigator Award supported my launch as an independent investigator and fueled my discovery of glutamate-modulating compounds with rapid action in OCD. I am forever grateful for the generosity and kindness of donors for both supporting the Foundation and my passion for pioneering treatments that rapidly relieve the suffering of individuals with serious mental illnesses.”
In another confirmation of the excellence that BBRF saw in Dr. Rodriguez a decade ago, in July 2019, she was selected as a recipient of the Presidential Early Career Award for Scientists and Engineers. The award recognizes investigators who are pursuing bold and innovative projects at the early stages of their careers and is considered one of the highest honors in scientific research.
A SPARK THAT IGNITES
Much like Carolyn Rodriguez, Kay M. Tye performed spectacularly well in her academic training, which began auspiciously at the Massachusetts Institute of Technology, where she earned a bachelor’s degree in Brain and Cognitive Sciences. She went on to the University of California, San Francisco, where she earned a Ph.D. in Neuroscience in 2008. She was winning prizes, awards, and recognition all along the way. After completing her postdoctoral training in the Stanford lab of Karl Deisseroth, M.D., Ph.D.—a BBRF Scientific Council member whose team is credited with development of the now widely adopted technology called optogenetics (helped by 2005 and 2007 BBRF Young Investigator grants to Dr. Deisseroth)—Dr. Tye was in excellent position to launch a lab of her own.
Although during her postdoctoral years she had received support from the National Institute of Mental Health, Dr. Tye still faced the problem that all beginning researchers face, no matter how gifted. As she set up her lab at MIT and began to draw in promising postdocs of her own to help in her research, she can distinctly “remember my lab manager coming to me and saying, ‘So, the money flow—it’s all one-way right now,’ meaning ‘out,’ of course—and he said, ‘Can you work on that?’ It was definitely stressful.”
She was brand new to the field as an independent entity; and she figured one way to get funded would be to focus narrowly on something not too risky—“to build up preliminary data” to support applications for large federal grants. But that wasn’t her style; from the start she wanted her lab to have an interdisciplinary focus and that meant supporting various related, but distinct lines of investigation at once.
That’s why she applied for and received, among other start-up grants, a BBRF Young Investigator award, in 2013. She would use optogenetics, the technology she learned in the Deisseroth lab, to manipulate specific neurons, and specific pathways of neurons in rodents, using colored beams of laser light to switch them on and off to study how the manipulation of these elements of basic brain infrastructure affected behavior in a line of rodents that modeled anxiety disorder. Behind this project was what Dr. Tye calls the “valence question—how do we determine if something is good or bad?”
She explains that everything we do is a product of motivation, which itself has various drivers, positive and negative. How these assessments underlying motivation are represented in the brain and then put to work by neural networks to guide behavior—“this is really the seed of everything my lab has done from the time of that first BBRF grant,” she says.
And once again, the “multiplier effect” was evident. On the strength of this and related research, Dr. Tye applied for and received her first R01 career award from the NIH in 2014, and has been enjoying great success ever since. In 2018 she received a second, simultaneous R01 career-sustaining grant, to explore neural circuit mechanisms underlying social contact and social isolation, both of which are of central importance in brain and behavior disorders ranging from schizophrenia and depression, to anxiety and autism. Like Dr. Rodriguez, Dr. Tye, in 2016, was awarded the Presidential Early Career Award for Scientists and Engineers. She has also received the NIH Director’s New Innovator Award and the NIH Director’s Pioneer Award.
Thinking back to the time of her BBRF Young Investigator grant, Dr. Tye, who recently accepted a new faculty position at the Salk Institute of Biological Studies, says that “it allowed me to take more chances, put a few more irons in the fire,” as she contemplated how to assemble the data the NIH would need to justify a career award.
“You’re essentially unknown. You don’t have the luxuries established principal investigators get to enjoy. It’s almost like you’re saying: what makes a car go? Well, it’s the spark plug, the point of ignition. Yes, a car needs gas. But I like the metaphor of the spark plug. If I hadn’t gotten that early award and a few other start-up grants, it would have been like pushing the car uphill. I would never have been able to get the momentum. So I think it’s really important to give promising young investigators a chance to get the ignition going, to get the motor running. At that point, then it’s up to us to keep the tank full of gas—and that’s what the government enables us to do if all goes well.”
In 2016 Dr. Tye was recognized again by BBRF, receiving its Freedman Prize for Exceptional Basic Research. The prize cited work that traced back to the project supported by her 2013 Young Investigator grant. The vision it supported, which continues in Dr. Tye’s lab today, is exciting: to understand mechanisms underlying behavior well enough to design manipulations of neural circuits. These would “induce plasticity to potentially cure—not just treat—a disorder like anxiety,” Dr. Tye says. That translational goal, moving from research to new understanding to clinical applications that benefit patients, is what the entire game is about for her and her team.
In 2016 Dr. Tye was asked by Dr. Pardes and members of the BBRF Scientific Council, to join them on the Council. Dr. Tye proudly accepted, and therefore now finds herself in position to repay a debt. Council members volunteer their time to select 200 new Young Investigators each year, a task in which Dr. Tye now participates. Not so long after getting some “spark” for her own research program from a BBRF award, she now has the pleasure of helping to decide who will benefit from this consequential gift for years that stretch far into the future.
— Written By Peter Tarr
Carolyn Rodriguez, M.D., Ph.D.
Assistant Professor, Department of Psychiatry and Behavioral Sciences
Director, Translational OCD Research Program
Stanford University School of Medicine
2014, 2009 Young Investigator
Kay M. Tye, Ph.D.
Whitehead Professorship Chair
Salk Institute for Biological Studies
BBRF Scientific Council Member
2016 Freedman Prizewinner for Exceptional Basic Research
2013 Young Investigator