Category: Uncategorized

Stopping Influenza with Flu-Glue

Today, a multidisciplinary team of researchers at the University of Washington, Fred Hutch, and The Scripps Research Institute published in Nature Biotechnology the computational design of a trimeric influenza-neutralizing protein that binds extremely tightly to the H3 hemagglutinin of 1968 Hong Kong pandemic influenza virus (A/Hong Kong/X31/1968). It also cross-reacts with human relevant H1, H2 and H3 influenza strains.

Figure 1. Design Process for Flu-Glue, a Potent Computationally Deigned Anti-Flu Protein.

 

 

 

 

 

The research has been recognized by opinion leaders and media outlets as a major step in the fight against the flu.  See articles in Science , the Conversation, and Scientific American, C&EN News.

Crafted in the Baker lab at the Institute for Protein Design, the protein affectionately known “Flu-Glue” was shown by the Fuller lab at UW to completely protect mice when given as a single intranasal dose 24 h before or after lethal challenge with H3N2 influenza.   The Bloom lab at the Fred Hutch has also shown that Flu-Glu has broad specificity to block both H3 and H1 viruses in vitro.   Also, Flu-Glue can both capture and detect hemagglutinin in a low cost paper-based diagnostic assay developed in collaboration with the Yager lab at the UW.

How does it work?

As illustrated in Figure 1, researchers designed this potent protein in a two-stage process.  They first used Rosetta computational design algorithms to generate a soluble protein that binds with reasonable affinity to the sialic acid binding pocket of the virus’ hemagglutinin protein (HA).  This is the site of receptor binding for virus which enables it to grab onto the surface cells and infect them.  In a second step, researchers then went on to design a homo-oligomeric trimeric version of the protein that self-assembles to optimally position three the binding proteins to match with near atomic level accuracy the three sialic acid binding pockets in of the self-assembled HA trimer—this is the natural form of HA on the surface of the virus.  By perfectly pre-arranging three low affinity HA binders to match three identical pockets on the surface of HA, the team achieved very tight binding to flu HA.  The Wilson lab and Ward lab at TSRI confirmed these structures by X-ray crystallography and cryo electron microscopy.

Why is it important?

Many viruses such as Ebola, influenza, respiratory syncytial virus, and others use a trimeric architecture for their cell surface receptor binding proteins.  This work proves that protein design can achieve very tight binding to such viral proteins with prophylactic, therapeutic, and diagnostic application.  While it is known that antibodies can bind and neutralize viral receptor proteins, their dimeric architectures are not suited to achieve the exquisite affinity and virus blocking ability of of the computationally designed trimeric Flu-Glue.

 

Arzeda Scales its Automated Molecule Development Pipeline

arzeda_logoSeattle-based Arzeda, a computational and synthetic biology company that was spun out from the University of Washington labs of Prof. David Baker, recently announced that its high-throughput, automated pipeline for protein engineering and pathway discovery had been validated by the production of two keystone molecules.

The announcement is a major technical milestone for Arzeda’s approach and their partnership with Amyris, Inc, which is part of a Defense Advanced Research Projects Agency (DARPA) Technology Investment Agreement (TIA).

The two molecules developed with the Arzeda technology are industrially important as dyes, food ingredients and pharmaceutical intermediates, but their current manufacture involves the use of highly toxic and carcinogenic substances such as cyanide and benzene.

“Arzeda’s computational design and synthetic biology technologies for protein design and pathway prediction can now leverage natural fermentation to produce molecules previously only produced through organic chemistry,” said Alexandre Zanghellini, co-founder and CEO of Arzeda. “We can also optimize them in ways not accessible to the synthetic chemist, creating the next generation of products with improved performance. Arzeda’s proprietary technology ushers in a new era of “combinatorial biochemistry” where entirely novel molecules can be made to order. We look forward to working with Amyris to further develop this important technology.”

 

Prof. Baker, currently the director of the Institute for Protein Design, helped co-found Arzeda, along with Drs. Alexandre Zanghellini, Eric Althoff and Daniela Grabs-Röthlisberger in 2008 to commercialize an innovative computational enzyme design technology based on the Rosetta software, that is used to rapidly make proteins and enzymes with new function.

These proteins and enzymes, and the more efficient and sustainable production pathways developed by Arzeda, have the potential to revolutionize industries ranging from food and pharmaceuticals, to advanced materials and chemicals.

Since its founding, Arzeda has been harnessing the technology to create new enzymes and chemical products that can compete on cost, performance and sustainability. The company has also established partnerships with several leading companies that will help bring these new products to the market.

Dr. Baker and the IPD continue to support Arzeda’s efforts to commercialize these important technologies, and look forward to more great news from Dr. Zanghellini and his team.

More information about Arzeda’s announcement is available at their website.

Limb Girdle Muscular Dystrophy Day and New Foldit puzzle

lgmdToday is Limb Girdle Muscular Dystrophy Day, and the Institute for Protein Design is collaborating with the Jain Foundation and Foldit community to to model the structure of human dysferlin protein (DYSF), an important protein for normal muscle function.  Numerous mutations in the gene that encodes DYSF protein are known to be the cause of Limb Girdle Muscular Dystrophy.  Our goal is first to first gain a better understanding of the structure of DYSF and then to use the structural information to investigate the effects of LGMD disease mutations on DYSF structure and function.

Read more on DYSF and LGMD at UW’s NewsBeat’s release here and Foldit’s release here.

Icosahedral protein nanocage – new paper and podcast

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The Baker lab, in collaboration with Neil King, Trisha Davis and Tamir Gonen’s labs, recently had a paper published in Nature about a stable icosahedral nanocage whose applications could span anywhere from drug delivery to vaccine design! The title is “Design of a hyperstable 60-subunit protein icosahedron” and it was published online June 15, 2016. Yang Hsia, a graduate student in David’s lab, gave an interview to Nature that was put in to a podcast that you can listen to here (called “Protein Football”).

See below for the abstract, or read the whole paper at Nature‘s website here or the Baker lab website here. There is also a great write up of the paper done by Chemical & Engineering News, which you can find here.

The icosahedron is the largest of the Platonic solids, and icosahedral protein structures are widely used in biological systems for packaging and transport1, 2. There has been considerable interest in repurposing such structures3, 4, 5 for applications ranging from targeted delivery to multivalent immunogen presentation. The ability to design proteins that self-assemble into precisely specified, highly ordered icosahedral structures would open the door to a new generation of protein containers with properties custom-tailored to specific applications. Here we describe the computational design of a 25-nanometre icosahedral nanocage that self-assembles from trimeric protein building blocks. The designed protein was produced in Escherichia coli, and found by electron microscopy to assemble into a homogenous population of icosahedral particles nearly identical to the design model. The particles are stable in 6.7 molar guanidine hydrochloride at up to 80 degrees Celsius, and undergo extremely abrupt, but reversible, disassembly between 2 molar and 2.25 molar guanidinium thiocyanate. The icosahedron is robust to genetic fusions: one or two copies of green fluorescent protein (GFP) can be fused to each of the 60 subunits to create highly fluorescent ‘standard candles’ for use in light microscopy, and a designed protein pentamer can be placed in the centre of each of the 20 pentameric faces to modulate the size of the entrance/exit channels of the cage. Such robust and customizable nanocages should have considerable utility in targeted drug delivery6, vaccine design7 and synthetic biology8.

IPD at Xconomy’s EXOME’s Seattle’s Life Science Disruptors 2016

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On Monday, representatives from the IPD spoke on a panel at Xconomy’s EXOME’s Seattle’s Life Science Disruptors 2016 event. It was titled “Proteins Like You’ve Never Seen” and included Lucas Nivon (Cyrus), Ingrid Swanson Putlz (PvP Biologics), Aaron Chevalier (Virvio), and David Baker. The event’s description was as follows:

Seattle is one of the few cities in the world with a dense confluence of biotechnology, medicine, information technology, and public health expertise, and a footprint small enough to encourage intense collaboration between the sectors. From that mix come new ideas, products, and organizations that aim to change the way new therapies are created are created and how people in the U.S. and around the world get their healthcare.

On May 2, we’ll gather at the Fred Hutchinson Cancer Research Center to hear from and talk to some of the most forward-thinking scientists, executives, entrepreneurs, and investors from Seattle and beyond whose work is shaking up entrenched healthcare practices. New drugs. Global initiatives. Better prevention and diagnosis. Deeper analysis. Join us for a healthy dose of thought-provoking conversation.

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Franziska Seeger @ Ignite Seattle

On February 18th, WRF Fellow Franziska Seeger gave a talk about proteins at Ignite Seattle. Presenters have 5 minutes to speak to the audience and deliver whatever point they are trying to get across. They also cannot control their slides, so they have to have their timing perfect. Talk about pressure! However, we believe that Franziska did an excellent job explaining “Molecular Machines and Designer Drugs.” Please see below to watch her presentation.

July IPD News Roundup

 

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RESEARCH

In an article out in Structure, Baker lab postdoc Dr. Hahnbeom Park in collaboration with IPD Assistant Professor Frank DiMaio investigate the origin of protein structure refinement from structural averaging at the residue level. Structure refinement has long been a challenge in the field of protein structure prediction and it aims to improve homology models to the level of experimentally determined structures. Their studies and conclusions can be found in a paper titled “The Origin of Consistent Protein Structure Refinement from Structural Averaging“.

Liangcai copyINSTITUTE

A big welcome to new UW Biochemistry and IPD Assistant Professor Dr. Liangcai Gu! Dr. Gu is also an Adjunct Assistant Professor of Genome Sciences. Dr. Gu’s lab is interested in using quantitative protein interaction profiling to understand molecular recognition and guide computation protein design. We are very excited to have Dr. Gu as part of our protein design team!

The IPD also welcomes visiting scholar Wally Novak, VISIT intern Can Li, and visiting research scientist Maziar Ardejani!

David Baker gave a talk at the Institute for Systems Biology in Seattle titled “Post-Evolutionary Biology: Design of novel protein structures, functions, and assemblies”.

Dr. Roman Jerala, from the National Institute of Chemistry in Ljubljana, Slovenia visited the IPD and gave a talk on “Design of modular topological folds”.

June IPD News Roundup

RESEARCH

A new Science paper is out from Dr. David Baker and IPD collaborator Dr. Tamir Gonen (HHMI Janelia Campus) titled Design of ordered two-dimensional arrays mediated by noncovalent protein-protein interfaces. Graduate student Shane Gonen and Dr. Frank DiMaio describe a new computational approach to design two-dimensional protein arrays with a number of exciting potential applications in materials, engineering, and diagnostics.

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INSTITUTE

cyrus1_cropJune was an exciting month for the IPD Translational Investigator program! The IPD launched its very first spinout – Cyrus Biotechnology. Founded by former IPD postdocs Drs. Lucas Nivon and Yifan Song, and former Baker lab graduate student Dr. Javier Castellanos, Cyrus aims to pursue commercialization of an innovative user friendly software as a service (SaaS) cloud computing solution for distribution of the powerful “Rosetta” protein structure prediction and design algorithms. Read the IPD’s full announcement here and explore the Cyrus website at www.cyrusbio.com for more information.

Congratulations to Baker lab graduate student Austin Day on his successful PhD thesis defense!

Translational Investigators along with Dr. Lance Stewart, IPD Sr. Director of Strategy, shared advancements in IPD research at the widely attended WBBA Life Science Innovation Northwest (LSINW) this month. LSINW “connect world-class industry leaders and showcases the Pacific Northwest as a global center for life science advancement”

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Cyrus Bio founder Dr. Lucas Nivon and UW CoMotion’s Josh Pan at LSINW 2015
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Translational Investigator Dr. Ingrid Swanson Pultz before her presentation on an oral therapeutic for celiac disease at LSINW 2015

IPD Launches First Company Spinout

Seattle, WA

cyrus1_cropToday, we are announcing that Cyrus Biotechnology, has been successfully launched from the UW Institute for Protein Design (IPD) to pursue commercialization of an innovative user friendly software as a service (SaaS) cloud computing solution for distribution of the powerful “Rosetta” protein structure prediction and design algorithms.

Cyrus is the first new IPD spin out, graduating from the IPD’s Translational Research program in less than 12 months from inception,” said Dr. David Baker, Director of the IPD. Cyrus is building a custom-designed protein modeling and design GUI, automating complex user procedures and deploying on the cloud to customers in Pharma, Biotech and the Chemical industries.

The company’s name was inspired by Cyrus Levinthal’s famous paradox, that most small proteins fold spontaneously on short time scales of less than a millisecond, despite there being are a very large number of degrees of freedom in an unfolded protein chain of amino acids, leading to an astronomical number of possible conformations that may need to be sampled before folding into a low energy conformation. The Rosetta suite of algorithms that originated over 15 years ago at the UW, now with a team of over 100+ programmers contributing to the Rosetta Commons, in many cases solves Levinthal’s paradox.

The IPD initiated its Translational Investigator program in April 2014 with $1.4 M in Opportunity Grant funding from the Life Science Discovery Fund (LSDF) and matching commitments of $5.2 M from the UW, Washington Research Foundation, and the generosity of local philanthropists. In addition to the Cyrus project, IPD Translational Investigator research programs include an oral therapeutic for celiac disease, flu viral therapeutics and diagnostics, and others in development. The Translational Investigator research programs enable talented postdoctoral fellows and graduate students to apply protein design research towards the challenge of real world problems, transitioning protein design research discoveries into Seattle area startup companies. The combination of LSDF Opportunity Grant funding with philanthropist matching funds is being applied to several ongoing translational projects.

With our LSDF funding, matching grants from philanthropists, and funding from the National Science Foundation I-Corps program, the IPD was able to support the Cyrus co-founder team from the inception of concept to launch of a new Seattle area startup company, all in collaboration with CoMotion and several stakeholders,” said Dr. Lance Stewart, Senior Director of Strategy for the IPD, who also serves as a mentor and advisor to the Translational Investigators.

The Cyrus translational project was conceived in April 2014 by Dr. Lucas Nivon, then a postdoctoral fellow in the Baker lab, together with two other Baker lab members, Dr. Yifan Song who at the time was a postdoc/acting instructor and Javier Castellanos who at the time was in his final year as a graduate student. Shortly after having conceived of the Cyrus concept, the co-founding team incorporated Cyrus and secured meetings with the W-Fund and the local WINGS angel investor network; together these investors have capitalized the IPD spin out with $850K in seed financing.

Throughout their 12 month incubation period, the Cyrus team completed the NSF I-Corps program, developed a prototype of the Cyrus platform, and worked with the UW CoMotion technology transfer office (Dr. Jennifer McCullar and Dr. Dennis Hanson, Senior Technology Managers) and the Rosetta Commons to secure the required intellectual property licensures needed to pursue the Cyrus business model.

“Dr. Jennifer McCullar was instrumental in working with RosettaCommons and CoMotion to facilitate our license negotiations,” said Dr. Lucas Nivon, CEO and Co-Founder of Cyrus. “Our company intends to change the way drugs are discovered by biotechnology and pharmaceutical companies, from a wet lab intensive effort to a computer-aided-design (CAD) engineering task enabled by cloud based Rosetta drug design and discovery.”

The last day of work at the UW for Lucas, Yifan, and Javier was May 1, 2015, when they transitioned to the Cyrus facilities in WeWork at South Lake Union. We wish them the very best.

Cyrus Biotechnology
www.cyrusbio.com

Read the UW CoMotion press release here.

May IPD News Roundup

P-icon-colorThe May IPD News Roundup covers a new Science paper from IPD Assistant Prof Frank DiMaio, a KOMO News interview with Translational Investigator Ingrid Swanson Pultz on celiac disease, and much more! At the link.

New structure solved for hyperthermophilic DNA virus

A new Science paper is out from IPD faculty Dr. Frank DiMaio titled A virus that infects a hyperthermophile encapsidates A-form DNA. Read the abstract below and the article at the link: http://www.sciencemag.org/content/348/6237/914.full.pdf

Extremophiles, microorganisms thriving in extreme environmental conditions, must have proteins and nucleic acids that are stable at extremes of temperature and pH. The nonenveloped, rod-shaped virus SIRV2 (Sulfolobus islandicus rod-shaped virus 2) infects the hyperthermophilic acidophile Sulfolobus islandicus, which lives at 80°C and pH 3. We have used cryo–electron microscopy to generate a three-dimensional reconstruction of the SIRV2 virion at ~4 angstrom resolution, which revealed a previously unknown form of virion organization. Although almost half of the capsid protein is unstructured in solution, this unstructured region folds in the virion into a single extended a helix that wraps around the DNA. The DNA is entirely in the A-form, which suggests a common mechanism with bacterial spores for protecting DNA in the most adverse environments.

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The SIRV2 protein dimer helices fully encapsulate the DNA. (A) Three asymmetric units of the virion are shown, illustrating how the N-terminal helices wrap around the DNA, forming antiparallel helix-helix packing. (B) Side view. (C) Surface view of the protein (using a 1.4 Å probe radius). (D) The right-handed solenoidal supercoiling of the DNA, with three turns shown.

 

 

AAAS 2015 Plenary Lecture by David Baker

David Baker, IPD Director and Professor of Biochemistry at the UW was the Plenary Speaker at this year’s AAAS meeting in San Francisco. A video of his talk, titled ‘Post-Evolutionary Biology: Design of Novel Protein Structures, Functions, and Assemblies’ covers a breadth of information on ongoing IPD research and can be viewed at the following link: http://www.aaas.org/annual-meeting/2015/plenaries/post-evolutionary-biology-design-novel-protein-structures-functions-assemblies

November IPD News Roundup

Twitter_UWproteindesignStaff and scientists of the IPD and Foldit volunteered at Pacific Science Center’s Life Sciences Research Weekend this month – teaching budding scientists about the awesomeness of protein folding! Pics from the event and more Institute news at the link.

IPD Mini Symposium 2014

The UW Institute of Protein Design (IPD) presents a Mini Symposium on “Sweet Spots for Designed Proteins as Therapeutics” on Weds Dec 10 at 9 AM in HSB D-209. Follow the link to get more details! We hope to see you there!

 

Custom design of novel alphahelical bundles

Three helix bundle thumbnailA new paper is out in this week’s issue of Science entitled High thermodynamic stability of parametrically designed helical bundles. Using novel computational design methods, extremely stable helical bundles can be custom designed with fine-tuned structural geometries for a number of applications. Read more about this exciting work at this link.

Women in Science Lunch Discussion

Women in Science lunch_smallA recent Nature issue exposed the dismaying fact that many women are deterred from pursuing a career in science, especially at the highest levels (postdoctoral positions, faculty position, scientific advisory boards to start up companies, etc). To talk about this significant gender gap in science and the issues female scientists face, Baker lab members participated in an informal lunch discussion to determine what specific steps could be taken as a group to encourage and promote women within our own scientific community. Learn more at this link.

WRF Awards $8M for the IPD Innovation Fellows Program

May 15, 2014

With a very generous $8 M gift from the Washington Research Foundation (WRF), the IPD has launched the WRF-IPD Innovation Fellows Program supporting research partnerships between the IPD and other Seattle-area research institutes or UW departments.  We are recruiting exceptionally talented researchers who have just finished their PhD to join expert laboratories at local institutions where they will apply protein design methods to current health, energy, and materials related research problems.  For more information see our web page here.  See additional news from UW here, PSBJ here, Xconomy here, and from Crosscut here.

WRF-IPD Innovation Fellows

Beyond Evolution: Protein Design News and Art

Flu BinderRe/Code writer James Temple has written an interesting article on David Baker’s efforts to design a new world of proteins.  The article covers the IPD efforts to design proteins that neutralize the flu virus, Alzheimer’s disease amyloid protein, and how the IPD is engaging citizen scientists in the Rosetta@home and Foldit projects.  Learn more at this link.

UW to Establish Institute for Protein Design

IPDDr. Paul Ramsey, CEO of UW Medicine, announces the establishment of the Institute for Protein Design (IPD).   “A major challenge for designing proteins for specific purposes is predicting three-dimensional shape from the amino acid sequence. Dr. David Baker, UW professor of biochemistry and an investigator of the Howard Hughes Medical Institute, has had remarkable success in making these predictions and in designing new proteins with new functions.”  

Baker will serve as the director or the IPD which will coalesce and expand existing strengths within the UW and Seattle. The IPD will integrate UW expertise in biochemistry, engineering, computer science and medicine, and leverage local strength in the software industry to design a whole new world of synthetic proteins that address challenges in medicine, energy and technology.

See full press release and additional information at this link.