Hugh O'Neill's lifelong fascination with the complexities of the natural world drives his research at the Department of Energy's Oak Ridge National Laboratory, where he's using powerful neutron beams to dive deep into the microscopic realm of biological materials and unlock secrets for better production of domestic biofuels and bioproducts.
As director of the Center for Structural Molecular Biology , or CSMB, at ORNL, O'Neill stewards neutron science capabilities that let researchers non-destructively probe the structure and behavior of living cells and proteins at the nano scale. CSMB is one of 10 structural biology and imaging resources of the DOE Office of Science's Biological and Environmental Research Program.
The CSMB centerpiece is the Biological Small-Angle Neutron Scattering instrument, or Bio-SANS, the only neutron instrument of its kind dedicated to studying biological samples. This and other CSMB facilities at ORNL give scientists a detailed view of the 3D shapes of large biological molecules and their complex processes.
O'Neill, who is also group leader for Biological Labeling and Scattering at ORNL, first connected with the CSMB in 2010, when he used Bio-SANS to explore proteins involved in plant photosynthesis. More recently, O'Neill has been using the instrument and computer simulations to investigate the molecular processes at work in plant material fermentation.
His research is supported in part by the DOE Solvent Disruption of Biomass and Biomembranes Science Focus Area , also known as the Biofuels SFA. The SFA, led by ORNL, aims to provide fundamental insights into how solvents alter the structure and arrangement of plant cell walls and microbial membranes to improve biofuels production.
Getting a fix on shape-shifting proteins
"My plant cell wall research focuses on a couple of key areas," O'Neill said. "The first is how to break down plants to extract fuels. Others include how the cell wall is assembled, and in particular cellulose synthesis," or how plants form structural cellulose, the most abundant polymer on earth and a key target for production of domestic biofuels and products.
O'Neill's cellulose research is shifting toward a concentration on the role of proteins in the polymer's formation. He is especially interested in intrinsically disordered proteins - shape-shifting proteins that by their flexible nature can contribute to a range of cellular processes such as stress response. Scientists are interested in whether those proteins could be harnessed to, for instance, engineer plants more suited to efficient biofuel production.
"Small-angle neutron scattering is well suited to studying the dynamic assemblies of these flexible, disordered proteins compared to other structural characterization methods," O'Neill said. "With neutrons you can see the overall size and shape of disordered protein assemblies, and feed that data into computational simulations to achieve a model that reveals a complete picture of the protein's structure and function." O'Neill collaborates with the Center for Molecular Biophysics at ORNL to accomplish the simulations work using high-performance computing.
By focusing on plant cell research with neutrons, O'Neill and colleagues showcase broader ORNL capabilities supporting bioscience. The result has been projects focused on better plant-based building materials, electronics and packaging, as well as biomedical applications. This collaboration is enabled by the availability of ORNL's advanced neutron capabilities to researchers across the nation as DOE Office of Science user facilities.
O'Neill has led the CSMB since 2018, and recently oversaw the installation of robotic systems and custom software to improve Bio-SANS productivity. The new system quadruples the number of samples the instrument can measure automatically, accelerating scientific discovery.
Upgrades for more, and more complex, samples
The instrument has also been upgraded with three detectors that enable Bio-SANS to capture the entire spatial scale of a sample in one measurement. The team is now studying ways to enhance the instrument further to enable measurement of larger systems such as geological materials like rocks and sediments, and bigger structures in the plant cell wall that could support analysis of plant biomass thermochemical pretreatments in real time. Other enhancements are being considered to study samples at low temperatures to understand what happens when materials freeze, and rapid mixing techniques to examine protein kinetics.
O'Neill began his science career in Ireland, where he earned degrees in biochemistry at University College Dublin and developed an affinity for research while studying electron transfer in proteins as an undergraduate. His doctoral work at the university focused on the respiratory pathways of bacterial cells involved in fermentation. He came to ORNL as a postdoctoral researcher studying biological fuel cells in 1998, and was hired as a staff scientist in 2005.
ORNL "gives you the opportunity to work with people in many different fields, enabling a much broader perspective for better science," O'Neill said. At the CSMB, he works with physicists, chemists, structural biologists, biochemists and computational scientists. "ORNL's collaborative nature is one of its big strengths, one that you see across the national lab system. Because I work at a user facility, I get exposed to lots of different types of research. Helping others be successful and learning from the projects themselves is very rewarding."
His advice for young scientists? "Advocate for yourself, especially at the graduate student level. I'd also advise trying out the user facilities at the national labs, where you can take advantage of the multidisciplinary environment. You don't have to be an expert in everything; our colleagues will help you set up your experiment and work with your data."
UT-Battelle manages ORNL for the Department of Energy's Office of Science, the single largest supporter of basic research in the physical sciences in the United States. The Office of Science is working to address some of the most pressing challenges of our time. For more information, please visit energy.gov/science . - Stephanie Seay
