Lars Brandén Launches the First Core Facility at West Campus

Lars J. Brandén, Ph.D., calls himself a “jack-of-all-trades”—a description that says much about his job as the inaugural director of Yale’s Center for High Throughput Cell Biology (HTCB). Brandén came to Yale with a unique résumé and an invaluable mix of experiences spanning gene therapy research at the Karolinska Institutet in Stockholm, Sweden, and proteomics at Memorial Sloan-Kettering Cancer Center in New York City. In his most recent post as associate director of chemical genetics and director of the Columbia MLSCN at Columbia University’s Salzberger Genome Center, he launched a facility for high-throughput screening of compounds in cell-based assays—an equipment-intensive process that has positioned Brandén on the cutting edge of biomedical technology.

At Yale, the Karolinska-trained biologist has placed Yale’s first high-throughput screening facility on the fast track, managing in six months a start-up that normally takes well over a year. The outfitting and staffing of such a center is a highly specialized job, requiring an in-depth understanding of not only the science, but also how labs operate. Brandén has paid close attention to every detail of this project, including the design and assembly of the machines and computer systems that make advanced research possible.

The facility came online in 2008 with the ability to perform high-throughput RNAi screening, a “knock-down” technique that turns gene functions off one at a time so that researchers can to determine their impacts on a cell. “High-throughput technology is a really powerful tool,” Brandén explains. “By taking the key genes and understanding the pathways they are involved in, we can find novel attack points for disease.” This work has implications in many areas of research and will be a core service in support of the West Campus institutes as well as researchers on Science Hill and in Yale School of Medicine. The Yale HTCB core will also contract out to research labs in industry and other universities.

Researchers at the Yale Center for High Throughput Cell Biology review images of cellular processes at work. Equipment in this lab is able to capture 50,000 image sets per day. Clockwise from left are Steven Berman, Adrian Poffenberger, Lori Ortoleva-Donnelly, Lars Brandén, and Michael Wyler.

A quick tour of the center reveals the high-tech nature of Brandén’s work. The lab features four Tecan Freedom 200 platforms, custom-designed systems that use advanced robotics to rapidly process batches of more than 200,000 cell samples at a time. Results from the screen are then recorded and streamed into a database for further analysis.

These high-throughput screening platforms can dramatically accelerate the pace of research. Such capabilities are most often associated with the research and development divisions of large pharmaceutical companies; Yale is among only a handful of universities with access to this technology.

As a complement to the integrated platereaders on the Tecan platforms, the center houses state-of-the-art imaging equipment. Cell-based assays are designed so that each “hit” produces a detectable signal that can be read by an automated microscope and quantified. To examine multiple effects simultaneously, the center uses high-content imaging technology. A PerkinElmer Opera confocal imaging system is capable of harvesting over 40,000 high-resolution RGB image sets per day, allowing scientists to obtain a broader context for the processes they are exploring. The center also features two traditional wet labs for research and development, as well as equipment for storage and to prevent contamination.

The custom-built Tecan Freedom 200 platforms are the heart of the Yale HTCB core, using advanced robotics to process cell-based assays in plates with up to 1,536 samples at a time.

The center’s work is a high volume enterprise. Brandén estimates that his team will generate around 50 terabytes of data each year—enough to fill more than one hundred desktop computers. To manage this data, he has developed a robust bioinformatics program, which is led by Adrian Poffenberger, a bioinformatics expert who came to Yale from Southern Research Institute. By harvesting, analyzing, and maintaining this vast collection of data, they plan to build a foundation of knowledge that can help researchers better understand how organisms develop and function.

Brandén explains, “What I believe is going to come out of what we are doing here is a deeper understanding of the cell and how it works on a molecular level. We can then extrapolate that information onto different cell types, which will enable us not only to learn about signaling inside a cell but to eventually understand how the basic foundations of life, like organogenesis, might work.”

As the University begins to populate West Campus, appointing leaders like Brandén is a critical first step in realizing the site’s transformative potential. Indeed, as a result of his expertise, Brandén and his fifteen-member staff are already at work, and accomplishments at the Center for High Throughput Cell Biology will advance the pace of discovery at Yale during an auspicious time. Brandén says, “If you go back fifty years and take that time and the advancements that were achieved in five decades, the science community of today will be making that same progress in the next five years.”