The Natural Bridge
In 2013, Piotr Sliz and the team at SBGrid published a paper in eLife describing, for the first time in a formal, academic fashion, the SBGrid model. In existence since 2000, SBGrid now has a life of its own, with 250 members and several employees supporting its operations. “We have an excellent team in place,” says Sliz, SBGrid’s founder and director. “It’s almost self-propelling.”
But turning SBGrid into an international consortium hasn’t been Sliz’s only focus. During these past ten-plus years, he has advanced computing at HMS, expanded SBGrid beyond X-ray crystallography to include electron microscopy and nuclear magnetic resonance imaging, and launched an independent research lab focused on microRNA regulation of gene translation. He has managed such a multitude and variety of accomplishments by virtue of his unique blend of expertise in computing and structural biology and also his readiness to try something new.
After completing graduate studies in structural biology at the University of Toronto, Sliz signed on to provide computing expertise in the lab of Stephen Harrison and the late Don Wiley at Harvard University. To streamline his work, he created an informal computing support system. “For me, the game was to minimize the computer support effort and carve out as much time as I could for my own projects,” says Sliz, now associate professor of Pediatrics and in Biological Chemistry and Molecular Pharmacology at Harvard Medical School.
That system was so effective that it caught on across the lab’s multiple locations and spread as fellow post-docs ventured out to form their own labs. In 2002, Sliz moved with the Harrison Lab to Harvard Medical School and continued to support SBGrid. He also took on the computational challenges of other labs at HMS. Support for the X-ray crystallography labs came naturally, says Sliz, “but the major game change was electron microscopy.” To handle the challenges of this new method, Sliz put a computing cluster in place, and dramatically expanded the data capacity of the computing infrastructure. Sliz also had to adapt the software to work on the new computing resource.
In addition to providing computing support, Sliz also collaborated on the science. For instance, in a project with HMS researcher Tom Walz, Sliz applied molecular refinement techniques from X-ray crystallography to EM data to solve the aquaporin structure. “At the time, there were rapidly evolving techniques and there was a need for someone who could bridge between the hardware, software and knowledge of structural biology methods to put things together,” says Sliz, who also collaborated with Walz on solving the clathrin lattice, with Stephen Blacklow on the Notch complex and with Suzanne Walker on o-GlcNAc transferase (OGT).
After determining the high-resolution structure of OGT he also ran a 2 microsecond molecular dynamics simulation – one of the longest ever done in academia – to show how the GlcNAc transferase opens its conformation to bind with a peptide.
In 2009, Sliz established his own laboratory in the Department of Biological Chemistry and Molecular Pharmacology at HMS. One focus, supported by the National Science Foundation, was the development of high performance grid portal technologies for structural biology. His group developed the wide-search molecular replacement portal (WS-MR), a tool that uses the Open Science Grid infrastructure to perform molecular replacement searches against all protein domains in the Protein Data Bank. The portal technology they developed can now be extended to other structural biology applications that require massive computational resources.
Sliz also is pursuing crystallographic studies of microRNA biogenesis regulation. Biogenesis of all microRNAs is regulated by two major components, Microprocessor and Dicer. A small oncofetal protein called Lin28 further regulates processing of the let-7 family of microRNAs.
To study the interaction between Lin28 and let-7, Sliz first had to find a stable part of the flexible protein/RNA complex. “We used NMR to refine our constructs and eventually arrived at complexes that readily crystallized, ” says Sliz. His group eventually determined three high-resolution crystal structures of Lin28 in complexes with various let-7 microRNAs.
Today, the lin-28 pathway is a main focus in the Sliz laboratory, where structural studies of other components of the pathway are underway. Efforts also involve understanding whether this complex is druggable and, if so, a potential target for a cancer therapy.
Meanwhile, Sliz is exploring the potential for SBGrid to have an impact beyond the field of structural biology. With support from the HMS Tools-and-Technologies committee, he is evaluating the SBGrid software support model to determine if it can be extended to provide a general model of scientific software support for all groups at HMS. “The way we organize software, the way we provide support, that’s scalable to any HMS lab that uses five or ten applications,” he says. “There is an opportunity to evaluate if this model of software support is applicable to biomedical research in general.”
-- Elizabeth Dougherty