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Fearless in the Face of Anything New and Unexplored: SLAS Graduate Education Fellowship Grant Winner Advances Actin Array Concept

With support from an SLAS grant, an enterprising graduate student from the University of California, Berkeley (UC Berkeley) is building an assay to explore actin complexes that helps researchers explore answers to never-before-asked questions.

“When you design novel instrumentation, it unlocks a whole other world of inquiry,” says Julea Vlassakis, the 2017 recipient of the SLAS Graduate Education Fellowship Grant and a Ph.D. candidate at UC Berkeley. Vlassakis will use the $100,000 grant, to be awarded over two years, to maximize university resources to design a high-throughput, electrophoretic separation assay to allow quantitation of F- and G-actin in single cells.

“Actin is a key structural protein in cells that regulates almost everything in terms of how cells move, interact with each other and use signals to drive certain processes,” says Vlassakis, whose training focuses on quantitative bioinstrumentation and application to biological systems.

The first aim of Vlassakis’ research is to design and optimize a method for delivery of F-actin stabilization lysis buffer for high-throughput lysis and electrophoresis of G-actin. She plans to design a novel functional material for high-throughput, in-hydrogel detection of F- and G-actin from single cells, as well as conduct assay validation and application in a high-throughput, whole-genome screen to determine genes that protect actin filament stability. She is excited about SLAS’s support of this significant research that will fulfill an unmet need to accurately quantify distributions of F and G-actin in single-cells for evaluation of cancer therapies and elucidation of the role of sub-populations in underlying disease.

“The timing was critical and perfect in that I am looking to finish my Ph.D. soon and the grant will support this project through completion. I anticipate that it will open new opportunities,” says Vlassakis, whose winning concept emerged from 21 excellent proposals and candidates that represented 12 institutions and three countries. She collaborated on the grant application with her faculty mentor, SLAS Technology author and Innovation Award Finalist Amy E. Herr, Ph.D., who feels that this research is a good fit with SLAS’ mission to further life sciences discovery and technology.

“Being able to explore actin in an automated, large-scale way will give us new data that’s not really accessible with existing tools. We hope to complement existing data and fill a hole in our understanding of what’s happening inside the cell. Learning how actin complexes form and more about the kinetics of the complexes is something we’re interested in pushing forward,” says Herr, who is the principal investigator in bioinstrumentation for quantitative biology and medicine at UC Berkeley, as well as a Chan Zuckerberg (CZ) Biohub Investigator.

Herr adds that the challenging research suits the determined graduate student’s research style. “Julea works hard to become an expert. She determines where we need some new understanding or capability and is fully committed to understanding knowledge gaps that occur in life sciences discovery and technology,” Herr continues. “Through hard work and thoughtful consideration, Julea hones in on those gaps like a laser and works to find out as much as possible. She talks to other researchers to get perspectives that might not be shared in their formal written documents or publications.”

The SLAS Graduate Education Fellowship Grant offers Vlassakis greater flexibility in her research, “because it is tied to her as an individual and a specific schematic area, but not necessarily specific deliverables,” Herr continues. “Some grants and industry funding have set deliverables, but this grant will allow Julea to move toward a goal while maintaining some element of creativity, which is important in the most innovative research.”

Vlassakis’ area is one that, to Herr’s knowledge, no one has explored. “These single cell measurements in cytometry look at direct measurements of different protein complexes in a way that has specificity that is not attainable with conventional immunoassays,” she comments.

Developing Single-cell Studies of Actin

Vlassakis’ actin research launched when Andrew Dillin, Ph.D., a UC Berkeley professor in the Department of Molecular and Cell Biology, and a postdoctoral researcher in his lab, Ryo Higuchi-Sanabria, Ph.D., reached out to Herr seeking an opportunity to develop instrumentation for their work with actin. In the Dillin lab, Higuchi-Sanabria's research involves characterizing actin cytoskeletal decline during advanced aging and identifying key components dedicated to protect cytoskeletal integrity during stress and aging. What excites Vlassakis about the collaboration is the process of developing and answering questions from the ground up.

“Early on we started discussing that if Ryo could measure anything, what would he measure?” explains Vlassakis. “He was thrilled to be involved in these discussions. He could essentially custom order an experimental set-up if he wanted that would enable him to ask questions that others could not. This is especially powerful given how intensely curious and driven Ryo is as a researcher.”

Having discussions, searching the literature and planning a tool that would address limitations in the current methodologies was a major focus initially. In reading the literature, Vlassakis discovered that the existing gold-standard tool to assess the organization of actin at the single cell-level wasn't very accurate.

"The gold standard method for measuring those filaments versus individual proteins is a fluorescent stain that binds specifically to either F-actin’s long filaments or individual proteins, referred to as G-actin. Unfortunately, the stain competes with a variety of cancer drugs or binding proteins 0for the same sites on the actin proteins,” she explains. "There’s actually a lot of inaccurate information you can get by using these stains."

What emerged was a clear need for a tool that allows the researcher to physically separate the F- and G-actin and in the process dissociate any species that would not allow detection of one or the other. "We were able to use antibodies to bind specifically to the different actin species that we’ve separated," Vlassakis says. “Now we are in the process of validating and applying what we have learned to the questions that Ryo has about how stresses such as heat shock change the organization of actin in the individual cells. It’s a process that hasn’t been studied at the single cell level before,” she continues.

It’s important to gain this single-cell measurement, according to Vlassakis. “For a variety of processes, including cancer progression and response, there’s a wide variation in what happens to proteins from cell to cell,” she explains. “What types of protein are present and in what quantities change dramatically through disease progression. You want to be able to directly measure each individual cell’s protein and cell-to-cell variation.”

While it’s possible to get a bulk average of proteins present across a million cells, Vlassakis hopes to capture what proteins are present in any individual cell. “We want to actually identify outlier and rogue cells that drive certain responses, whether that is, in this case, heat shock response or potentially cancer drug resistance,” she explains.

Head Start in Higher Education

Vlassakis started work in the Harvard lab of Mara Prentiss, Ph.D., as a junior in high school when she attended the Commonwealth School, a small, independent school in Boston’s Back Bay. Her high school chemistry teacher, Rebecca Jackman, Ph.D., who knew Prentiss, connected Vlassakis to the position, which grew into a five-year relationship with the lab.

The first few exhilarating experiments, conducted under the guidance of experienced postdocs from around the world, were overwhelming. “They quickly rattled off the experimental conditions and stepped away. I had no clue what I was supposed to do!” Vlassakis says with a laugh. “In the spirit of doing research, you have to face inexperience and uncertainty and find a way to navigate it. You learn when to ask questions and know that it’s ok to have a trial by fire experience. I was definitely asked to do things that really pushed me, but I was fortunate to be granted autonomy to run experiments, explore and contribute during my time in the lab there.”

From high school and throughout her undergraduate summers at Smith College, Northampton, MA, where she earned a bachelor’s degree in chemistry and physics, what struck a chord with Vlassakis was the pioneering aspect of research and the amazing tools she used to make her discoveries.

“The first experiment I did as a high school student was to attach a DNA strand to a surface and a bead and use a magnet to apply force to the bead to stretch the DNA. We wanted to measure the mechanical response of the DNA under force to better understand these types of interactions with proteins,” she explains. “Mara stopped me at one point and said, you know you are one of only 10 people in the world to have done that experiment.”

The other aspects of the research that inspired her were the single-molecule, biophysical tools she used, such as optical and magnetic tweezers, which had only been in labs in their modern form for a short amount of time. This notion of adapting novel instruments to be on the cutting edge of discovery inspired her to pursue engineering in graduate school.

Immersion in Engineering

Jumping from her basic research background to graduate school in engineering posed an exciting challenge for Vlassakis. “In basic research, you’re applying the scientific method to investigate questions that you have determined are important to understand. In engineering, you use engineering design to guide your questions, determine whether there’s an unmet need that requires a new tool and iteratively design to achieve the measurement goal,” she explains.

Vlassakis decided early on that the road to success in this transition meant surrounding herself with generous mentors and colleagues. At the top of her list is Herr. “Amy’s mentorship has changed my life, and her infectious enthusiasm continues to inspire me. She provides thorough feedback on everything from fellowship applications and conference presentations to manuscripts,” Vlassakis says. “She’s the rare advisor who brings you a glass of water in the middle of a long poster presentation session anticipating you are likely thirsty.”

Vlassakis adds that another important part of her transition was learning not to compare herself to others. “It’s not a healthy practice for graduate students. You are a student; you’re supposed to be there to learn,” she comments. “There’s no need to constantly compare yourself to someone who has been doing something much longer than you have. Everyone has their own skill sets and experiences that make them who they are as researchers. You are constantly going to grow and improve.”

Once she found her footing in the engineering program, Vlassakis got involved in UC Berkeley’s Tekla Labs to bolster her engineering and organizational acumen, and lead a team to make science more accessible. Tekla Labs, an organization focused on developing and sharing blueprints to build scientific tools for use in low-resource settings worldwide, launched seven years ago. Student researchers at UC Berkeley and University of California, San Francisco (UCSF) visited university science labs in South America and found that the shortage of basic equipment inhibited scientific innovation.

Vlassakis’ first task was to grow the organization’s design library through an online blueprint contest that received more than 100 submissions from around the world. “We worked with a website called Instructables, an online host for the do-it-yourself maker community, where people submitted designs that ranged from benchtop centrifuges to the programmable temperature controller and hot plate design that won the grand prize,” she explains. Tekla received funding for the project from Big Ideas @ Berkeley, a program that supports interdisciplinary teams of students.

Another rewarding activity for Vlassakis is slipping into the instructor role. She traveled to the East Coast in Summer 2017 for a teaching stint at Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. “This is the second year that I have served as an instructor for the lab’s single-cell analysis course,” she says. “During the two-week long course, we introduce grad students and postdocs from around the world to the techniques we have developed in the Herr Lab, and they perform their own single-cell protein analyses.”

Vlassakis’ summer of ’17 also included chairing a Gordon Research Seminar, “Microfluidic Phenomena and Global Challenges,” in June in Lucca (Barga), Italy. The forum offered an opportunity for graduate students, postdocs and other scientists with comparable levels of experience and education to present and exchange new data and cutting-edge ideas before the start of a five-day Gordon Research Conference in which top professors in microfluidics shared their research.

“Students show posters during the main conference, but the pre-conference seminar gives them more opportunity to become comfortable communicating their work before they have to give presentations in front of their idols in the field,” Vlassakis explains. “In addition to the scientific portion of the seminar, we also build in a career development aspect with a panel of professionals from across academia and industry.” Having become acquainted with SLAS during the process of applying for the Fellowship Grant, Vlassakis invited SLAS CEO Vicki Loise to join the panel.

“Vicki brought a unique perspective of someone who has worked in management for many years, something that scientists and engineers sometimes miss – explicit discussions about management training,” says Vlassakis. “We get thrown into management and leadership positions by virtue of being good researchers, which is not the same skill set as being a good manager. It was interesting to hear her insights there.”

And it’s interesting for Vlassakis to explore what SLAS has to offer. “I’m happy to support this community in any way that I can. I am keeping my eyes and ears open to help out at SLAS2018 in San Diego,” she says.

Traveling Deep Waters

With so many irons in the fire, Vlassakis says it’s essential to step away and clear her head. To do this, she takes to the water. “I enjoying kayaking and being outside in fresh air,” she says. “It’s almost meditative to me to be out on the water. Everything I am grappling with in the lab seems to stay on the shore. It’s been a hobby that has helped me a lot in graduate school.”

Another way to get a good grip on her lab projects is to share her work with people outside of the field. “I enjoy explaining my research to my family back on the east coast. No one is a scientist, so it makes me think about my work in a different way,” she says. “A lot of the detail that I get caught up in on a day-to-day basis, while also important, kind of fades out of those discussions with family and friends who don’t do research. It boils the science down to its essence and helps me clarify it – especially when I get stuck.”

Adventurous in the face of anything new and unexplored, Vlassakis advises others to take on new challenges. “It’s important to just go for it when something speaks to you or when you are faced with an area that’s different from what you’ve pursued before,” she concludes. “If it seems exciting, don’t put on the brakes just because that’s not your field.”

Congratulations to the Top Five Finalists for the SLAS Graduate Education Fellowship Grant

Finalists for the 2017 SLAS Education Fellowship Grant are awarded SLAS Tony B. Academic Travel Awards for SLAS2018. Tony B. Award winners receive airfare, hotel and registration for the flagship SLAS International Conference and Exhibition. In addition to Vlassakis, the finalists are Ashley Fancher, a graduate student at the University of Pittsburgh, Pittsburgh, PA, Santosh Paidi, a graduate research assistant at Johns Hopkins University, Baltimore, MD, and Marie Malone, a graduate student at The Scripps Research Institute, La Jolla, CA.

The application process for the 2018 SLAS Education Fellowship Grant is open until Dec. 11, 2017. Visit SLAS Graduate Education Fellowship Grant Program for more information.

September 12, 2017