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  • New Algorithm Sharpens Focus of World’s Most Powerful Microscopes

    New Algorithm Sharpens Focus of World’s Most Powerful Microscopes

    In recent years, cryo-electron microscopy (cryo-EM) technology has advanced to the point that it can produce structures with atomic-level resolution for many types of molecules. Yet in some situations, even the most sophisticated cryo-EM methods still generate maps with lower resolution and greater uncertainty than required to tease out the details of complex chemical reactions.

    In a study published in Nature Methods, a multi-institutional team led by Tom Terwilliger from the New Mexico Consortium and including researchers from Berkeley Lab demonstrates how a new computer algorithm improves the quality of the 3D molecular structure maps generated with cryo-EM.

    Using the enzyme β-galactosidase, also called lactase, as a test case, the researchers applied the standard methods (a) and then applied the improvement algorithm without (b) and with a filter to improve the uniformity of noise in the map (c), both of these maps are more similar to the deposited high-resolution protein structure map (d). (Credit: Terwilliger et al./Nature Methods)
    Using the enzyme β-galactosidase, also called lactase, as a test case, the researchers applied the standard methods (a) and then applied the improvement algorithm without (b) and with a filter to improve the uniformity of noise in the map (c), both of these maps are more similar to the deposited high-resolution protein structure map (d). (Credit: Terwilliger et al./Nature Methods)

    The algorithm sharpens molecular maps by filtering the data based on existing knowledge of what molecules look like and how to best estimate and remove noise in microscopy data. An approach with the same theoretical basis was previously used to improve structure maps generated from X-ray crystallography, and scientists have proposed its use in cryo-EM before. But, according to study co-author Paul Adams, Director of the Molecular Biophysics and Integrated Bioimaging (MBIB) Division, no one had been able to show definitive evidence that it worked for cryo-EM until now.

    The authors note that the clear benefits of the algorithm in revealing important details in the data, combined with its ease of use – it is an automated analysis that can be performed on a laptop processor – will likely make it part of a standard part of the cryo-EM workflow moving forward. In fact, Adams has already added the algorithm’s source code to the Phenix software suite, a popular package for automated macromolecular structure solution for which he leads the development team.

    Read more in the Berkeley Lab News Center.

  • It’s All Connected: Your Genes, Your Environment, and Your Health

    It’s All Connected: Your Genes, Your Environment, and Your Health

    Human health is highly dependent on genetics, yet it is also known to be affected by factors in an individual’s environment. Statistician Paul Williams, a staff scientist in the Molecular Biophysics and Integrated Bioimaging (MBIB) Division, specializes in investigating the instances where genetics and environment are most closely intertwined. His work focuses on a phenomenon called “quantile-dependent expressivity,” which describes the relationship between the genes that predispose people to certain traits that can be amplified by environmental factors. He has recently published three separate studies on alcohol consumption, weight gain, and lung health that suggest that these facets of health are indeed affected by quantile-dependent expressivity. The findings were generated by analyzing datasets from the Framingham Study – a famous, ongoing health and lifestyle study that collects detailed records of diet, exercise, medication use, and medical history from thousands of families.

    Read more in the Berkeley Lab News Center.

  • Study Finds ‘Missing Link’ in the Evolutionary History of Carbon-Fixing Protein Rubisco

    Study Finds ‘Missing Link’ in the Evolutionary History of Carbon-Fixing Protein Rubisco

    Form I rubisco, an enzyme found in plants, algae, and cyanobacteria, has a deep evolutionary history going back nearly 2.4 billion years to the Great Oxygenation Event, when cyanobacteria transformed the Earth’s atmosphere by introducing oxygen through photosynthesis. Rubisco’s role in this foundational event makes it a key focus of scientists studying the evolution of life, as well as scientists seeking to develop bio-based fuels and renewable energy technologies.

    In a study appearing in Nature Plants, researchers from UC Davis, UC Berkeley, and Berkeley Lab report the discovery and characterization of a previously undescribed lineage of form I rubisco – one that the researchers suspect diverged from form I rubisco prior to the evolution of cyanobacteria. The novel lineage, called form I’ rubisco, gives researchers new insights into the structural evolution of form I rubisco, potentially providing clues as to how this enzyme changed the planet.

    The work was led by Patrick Shih, a UC Davis assistant professor and the director of Plant Biosystems Design at the Joint BioEnergy Institute (JBEI), and Doug Banda, a postdoctoral scholar in his lab.

    Study co-author and collaborator Jill Banfield, of UC Berkeley’s Earth and Planetary Sciences Department, uncovered form I’ rubisco after performing metagenomic analyses on groundwater samples. Metagenomic analyses allow researchers to examine genes and genetic sequences from uncultured microorganisms found in the environment.

    Using the genes and genetic sequences provided by Banfield, who is also a Berkeley Lab faculty scientist with a secondary appointment in Biosciences’ Environmental Genomics and Systems Biology (EGSB) Division, Banda and Shih successfully expressed form I’ rubisco using E. coli.

    To learn how this newly identified form functions and how it compares to previously discovered rubisco enzymes, the scientists needed to build precise, 3D models of its structure. For this task, the lead authors turned to Paul Adams, Henrique Pereira, and Michal Hammel in the Molecular Biophysics and Integrated Bioimaging (MBIB) Division.

    A ribbon diagram (L) and molecular surface representation (R) of carbon-fixing form I’ rubisco, showing eight molecular subunits without the small subunits. An x-ray diffraction pattern of the enzyme, also generated by the research team, is in the background. (Credit: Henrique Pereira/Berkeley Lab)
    A ribbon diagram (L) and molecular surface representation (R) of carbon-fixing form I’ rubisco, showing eight molecular subunits without the small subunits. An X-ray diffraction pattern of the enzyme, also generated by the research team, is in the background. (Credit: Henrique Pereira/Berkeley Lab)

    First, Adams and Pereira performed X-ray crystallography – an approach that can generate images of molecules with atomic-level resolution – at Berkeley Lab’s Advanced Light Source (ALS). Then, to capture how the enzyme’s structure changes during different states of activity, Hammel applied a technique called small-angle X-ray scattering (SAXS) using the SIBYLS beamline at the ALS.

    The ALS investigations showed that like form I rubisco, form I’ rubisco is built from eight large subunits. However, it doesn’t possess the small subunits that were previously thought to be essential to its carbon-fixing function. The researchers now believe that form I’ rubisco represents a missing link in the evolutionary history of form I rubisco’s structure.

    Read more in the Berkeley Lab News Center.

  • Plant Single-cell Solutions for Energy and the Environment Workshop Report Released

    Plant Single-cell Solutions for Energy and the Environment Workshop Report Released

    On January 23, 2020, Berkeley Lab hosted a workshop on opportunities afforded by single-cell technologies for energy and environmental science, as well as conceptual and technological grand challenges that must be tackled to apply these powerful approaches to plants, fungi and algae. This event brought together a diverse group of leaders in functional genomics technologies from academia, the National Laboratories, and local research institutions.

    The workshop included presentations and breakout sessions to explore applications of single-cell technology, including: powering higher-resolution studies of plant responses to environmental stimuli; improving the functional annotation of genes across tissues and species; and optimizing bioproduct and biomaterial production. Attendees expressed overwhelming support for the creation of a centralized, open-access database to house plant single-cell data, analogous to the Human Cell Atlas, and considered how such an effort should balance the need for deep characterization of a few important model species while still capturing the broader diversity in the plant kingdom.

    The organizing committee was chaired by Diane Dickel, staff scientist in the Environmental Genomics and Systems Biology Division. Additional committee members were Ben Cole, Rex Malmstrom, Jenny Mortimer, Chris Mungall, Ronan O’Malley, and Axel Visel.

    The workshop report is available for download; a peer-reviewed Perspectives article was published in Communications Biology.

  • Doudna Awarded 2020 Nobel Prize in Chemistry

    Doudna Awarded 2020 Nobel Prize in Chemistry

    Jennifer DoudnaBiochemist Jennifer Doudna, a professor at UC Berkeley and faculty scientist in the Molecular Biophysics and Integrated Bioimaging Division, has been awarded the 2020 Nobel Prize in Chemistry for “the development of a method for genome editing.” She shares the Nobel Prize with co-discoverer Emmanuelle Charpentier, who currently serves as the scientific and managing director of the Max Planck Unit for the Science of Pathogens in Berlin. Together, they form the first all-woman research team to be recognized with a Nobel Prize.

    Doudna’s CRISPR work builds on her long history of studying various aspects of RNA, which includes some Laboratory Directed Research and Development (LDRD)-funded work on CRISPR RNA strands and the Cas1 protein. In 2012, Doudna and Charpentier’s research team detailed the underlying mechanisms of the CRISPR-Cas9 system – a component of the bacterial immune system that defends against invading viruses – and explained how it can be programmed to cut DNA at a target sequence.

    Today, Doudna and Charpentier’s Nobel Prize-winning CRISPR-Cas9 technology is the basis of many promising medical technologies, including tools to diagnose and treat infections, and has many applications for the development of improved crops, biofuels, and bioproducts.

    Read more in the Berkeley Lab and UC Berkeley press releases.

  • JGI Helps Find Shattering Gene in Wild Setaria Populations

    JGI Helps Find Shattering Gene in Wild Setaria Populations

    Green millet plants growing at the Danforth Center. (Bruton Stroube/ Donald Danforth Plant Science Center)
    Green millet plants growing at the Danforth Center. (Bruton Stroube/ Donald Danforth Plant Science Center)

    Innumerable road trips to collect hundreds of weedy green millet (Setaria viridis) plants have resulted in a Nature Biotechnology paper from researchers at the DOE Joint Genome Institute, the Danforth Center and the HudsonAlpha Institute for Biotechnology. The team generated genome sequences for nearly 600 green millet plants and released a very high quality reference S. viridis genome sequence. Analysis of these plant genome sequences also led researchers to identify a gene related to seed dispersal in wild populations for the first time. Learn more here on the JGI website

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  • Transforming Waste into Bio-based Chemicals

    Transforming Waste into Bio-based Chemicals

    Researchers make important step towards converting a material in plant cell walls into eco-friendly ionic liquids

    Researchers at Berkeley Lab have transformed lignin, a waste product of the paper industry, into a precursor for a useful chemical with a wide range of potential applications.

    Lignin is a complex material found in plant cell walls that is notoriously difficult to break down and turn into something useful. Typically, lignin is burned for energy, but scientists are focusing on ways to repurpose it.

    In a recent study, researchers demonstrated their ability to convert lignin into a chemical compound that is a building block of bio-based ionic liquids. The research was a collaboration between the Advanced Biofuels and Bioproducts Process Development Unit, the Joint BioEnergy Institute (both established by the Department of Energy and based at Berkeley Lab), and the Queens University of Charlotte.

    Ionic liquids are powerful solvents/catalysts used in many important industrial processes, including the production of sustainable biofuels and biopolymers. However, traditional ionic liquids are petroleum-based and costly. Bio-based ionic liquids made with lignin, an inexpensive organic waste product, would be cheaper and more environmentally friendly.

    “This research brings us one step closer to creating bio-based ionic liquids,” said Ning Sun, the study’s co-corresponding author. “Now we just need to optimize and scale up the technology.”

    According to Sun, bio-based ionic liquids also have a broad range of potential uses outside of industry. “We now have the platform to synthesize bio-based ionic liquids with different structures that have different applications, such as antivirals,” Sun said.

    This research was funded by DOE’s Bioenergy Technologies Office through the Technology Commercialization Fund.

    This Science Snapshot was published on the Berkeley Lab News Center.

  • Synthetic Pathways Turn Plants into Biofactories for New Molecules

    Synthetic Pathways Turn Plants into Biofactories for New Molecules

    Scientists demonstrate a method for sustainably producing a wide range of compounds

    Plants can produce a wide range of molecules, many of which help them fight off harmful pests and pathogens. Biologists have harnessed this ability to produce many molecules important for human health — aspirin and the antimalarial drug artemisinin, for example, are derived from plants.

    Now, scientists at the Joint BioEnergy Institute (JBEI) are using synthetic biology to give plants the ability to create molecules never seen before in nature. New research led by Patrick Shih, director of Plant Biosystems Design at JBEI, and Beth Sattely of Stanford University describes success in swapping enzymes between plants to engineer new synthetic metabolic pathways. These pathways gave plants the ability to create new classes of chemical compounds, some of which have enhanced properties.

    “This is a demonstration of how we can begin to start rewiring and redesigning plant metabolism to make molecules of interest for a range of applications,” Shih said.

    Engineering plants to make new molecules themselves provides a sustainable platform to produce a wide range of compounds. One of the compounds the researchers were able to create is comparable to commercially used pesticides in their effectiveness, while others may have anti-cancer properties. The long-term goal is to engineer plants to be biofactories of molecules such as these, bypassing the need to externally spray pesticides or synthesize therapeutic molecules in a lab.

    “That’s the motivation for where we could go,” Shih said. “We want to push the boundaries of plant metabolism to make compounds we’ve never seen before.”

    JBEI is a DOE Bioenergy Research Center supported by DOE’s Office of Science.

    This Science Snapshot was published on the Berkeley Lab News Center.

  • Providing New Technologies for Vaccine Development

    Providing New Technologies for Vaccine Development

    Berkeley Lab scientists aid in quest to design novel vaccine scaffolds

    Vaccines, which help the body recognize infectious microorganisms and stage a stronger and faster response, are made up of proteins that are specific to each type of microorganism. In the case of a virus, viral proteins – or antigens – can sometimes be attached to a protein scaffold to help mimic the shape of the virus and elicit a stronger immune response. Using scaffolds to approximate the natural configuration of the antigen is an emerging approach to vaccine design.

    A team of scientists led by David Baker at the University of Washington developed a method to design artificial proteins to serve as a framework for the viral antigens. Their study was published recently in the journal eLife. Berkeley Lab scientists collected data at the Advanced Light Source to visualize the atomic structure and determine the dynamics of the designed scaffolds.

    “When bound, the scaffolds assume predicted geometries, which more closely approximate the virus shape and thereby maximize the immune response,” said Banu Sankaran, a research scientist in the Molecular Biophysics and Integrated Bioimaging (MBIB) Division. “It was exciting to collaborate on this method to predictably design frameworks, which could lead to more effective vaccines, especially for viruses that we don’t have a scaffold for.”

    The team also included Peter Zwart, MBIB staff scientist; small angle X-ray scattering data were collected at the SIBYLS beamline by MBIB’s Kathryn Burnett and Greg Hura.

    The Advanced Light Source is a DOE Office of Science user facility.

    This Science Snapshot was published on the Berkeley Lab News Center.

  • Congratulations to Biosciences Area Director’s Award Recipients

    Congratulations to Biosciences Area Director’s Award Recipients

    Numerous Biosciences Area personnel are among the 2020 Berkeley Lab Director’s Awards honorees. This annual program recognizes outstanding contributions by employees to all facets of Lab activities. A complete list of winners can be found here. The ninth annual Director’s Awards ceremony will take place (virtually) on November 12 at 3 PM.

    Emiley Eloe-Fadrosh (JGI)Emiley Eloe-Fadrosh, head of the Metagenome Program at the Joint Genome Institute (JGI), will receive the Early Scientific Career award for her exceptional accomplishments in microbiome data science and for establishing the National Microbiome Data Collaborative (NMDC) as a resource in support of DOE’s science mission.

    Chris Mungall, head of the Biosystems Data Science Department in Environmental Genomics and Systems Biology (EGSB), will receive the Early Scientific Career award for his leadership of the design and development of collaborative, open-source, cross-cutting software and ontologies for tackling key scientific challenges, such as novel knowledge integration approaches to address COVID-19.

    JGI’s Lisa Kegg, Donald Miller, and Christine Naca, will receive the Operations award for their outstanding success in the planning and execution of the move of the JGI User Facility and KBase teams to the Integrative Genomics Building (IGB), as well as the restoration of JGI’s former Walnut Creek facility.

    JGI’s Massie Ballon, Alison Takemura, and Daniel Udwary will receive the Outreach award for conceiving, branding, and launching two podcast series—the Genome Insider and the Natural Prodcast—to improve new user and public engagement, and sustaining these series in the midst of a global pandemic.

    Jan-Fang Cheng, staff scientist at JGI, will receive the Service award for technological contributions essential to DOE’s success in the Human Genome Project; for developing a world-class single cell capability; and for establishing routine DNA synthesis at JGI. His contributions over the last 30 years have enabled endless scientific discovery through centralized genomic resource accessibility.

    Bob Glaeser, senior scientist in Molecular Biophysics and Integrated Bioimaging (MBIB), will receive the Tech Transfer award for his contributions to electron microscopy and cryogenic electron microscopy, which are distinguished by his foundational work in the field and his prolific portfolio of inventions. His work during an impressive 55-year career has accelerated this important area of science and its application in the pharmaceutical industry.

    In addition, Biosciences Lead Safety Coordinator Shraddha Ravani will receive the Safety award as part of an Advanced Light Source (ALS) team cited for their expertise, humor, and exceptional service to the ALS user community, enabling 2,000 scientists a year to safely perform outstanding research.

  • Machine Learning Takes on Synthetic Biology: Algorithms Can Bioengineer Cells for You

    Machine Learning Takes on Synthetic Biology: Algorithms Can Bioengineer Cells for You

    Tijana Radivojevic (left) and Hector Garcia Martin work on mechanical and statistical modeling, data visualizations and metabolic maps at the Agile BioFoundry.
    Engineering biological systems to specification–for example, designing a microbe to produce a cancer-fighting agent–requires a detailed mechanistic understanding of how all the parts of a cell work. Typically, this knowledge is acquired through years of painstaking work and a fair amount of trial and error. But Berkeley Lab scientists have created an Automated Recommendation Tool (ART) that adapts machine learning algorithms to the needs of synthetic biology to guide development systematically. With a limited set of training data, the algorithms are able to predict how changes in a cell’s DNA or biochemistry will affect its behavior, then make recommendations for the next engineering cycle along with probabilistic predictions for attaining the desired goal. The work was led by Hector Garcia Martin, a researcher in Berkeley Lab’s Biological Systems and Engineering (BSE) Division and Tijana Radivojevic, a BSE data scientist. In a pair of papers recently published in the journal Nature Communications, they presented the algorithm and demonstrated its capabilities.

    Read more in the Berkeley Lab News Center.

  • James Hurley Awarded $7M to Study Role of Mitophagy in Parkinson’s Disease

    James Hurley Awarded $7M to Study Role of Mitophagy in Parkinson’s Disease

    The Aligning Science Across Parkinson’s (ASAP) initiative has awarded James Hurley, a faculty scientist in the Molecular Biophysics and Integrated Bioimaging (MBIB) Division, $7 million over three years to investigate the role of damaged mitochondria in the disease. The grant is among 21, totaling $161 million, announced by the ASAP initiative, which aims to fund basic research to close gaps in our understanding of the mechanisms of Alzheimer’s Disease and its progression.

    Hurley, who is also a professor of molecular and cell biology at UC Berkeley (UCB), will lead a multi-institution interdisciplinary team that includes Eunyong Park of UCB, Erika Holzbaur of the University of Pennsylvania, Sascha Martens of the Max Perutz Labs in Austria, and Michael Lazarou of Monash University in Australia.

    According to Hurley, one of the most promising leads in Parkinson’s research involves two genes, PINK1 and Parkin, mutated variants of which are found in families with the hereditary form of the disease. Richard Youle at the NIH recently received the 2021 Breakthrough Prize for establishing that the normal function of these genes is to label damaged mitochondria for recycling (a process called mitophagy), and that mutations allow damaged mitochondria to accumulate, which leads to cell death.

    Hurley has studied cellular recycling for more than 10 years and will employ the techniques he has developed to study this process in its entirety. “We are going to dive deep and really work out in great, gory detail, atom by atom, exactly how the genes affect mitophagy at the level of precision that we would need to compute what steps you would have to change, and by how much, in a therapy,” he said.

    Read more from UC Berkeley News.