November 23, 2013
David Baker, Head of the Institute for Protein Design was recently in Toronto, Canada in late October to deliver a lecture on protein design as part of Gairdner Award celebrations. This was written up in the Globe and Mail, where Dr. Baker noted the tremendous citizen science contributions of over 300,000 Rosetta@home volunteers and Foldit players, 200 of which are regular contributors to protein designs that are more deeply explored at the Institute for Protein Design.
On Thursday, October 24, Gairdner’s annual program of lectures and symposia concluded with the annual Canada Gairdner Awards Dinner in Toronto.
Over 500 scientists, academics, and corporate and government leaders networked at the Royal Ontario Museum, and celebrated presentations of the four 2013 Canada Gairdner International Awards, the Global Health Award and the Wightman Award.
David Baker, left, and Sir Gregory Winter spoke to the Gairdner Foundation in Toronto on October 24, 2013
November 21, 2013
Thank you to our supporters. GIVING IN ACTION: Making Dreams Come True.
Barton Family Foundation, Life Sciences Discovery Fund,
Bruce and Jeannie Nordstrom, and Three Dreamers all supporting the IPD.
Thank you all for your help in supporting our efforts in protein design.
GIVING IN ACTION: Making Dreams Come True
November 2, 2013
Visit us on Facebook and follow us on Twitter @UWproteindesign
October 24, 2013
Prof. David Baker, Head of the UW Institute for Protein Design, HHMI Investigator provides an in depth discussion on the design of protein structures, functions and assemblies. Click here to watch the video.
David Baker – Design of protein structures, functions and assemblies
October 23, 2013
September 19, 2013
September 19, 2013
Brain cancer is a serious unmet medical challenge, and Washington state is one of the leading research clusters working on glioblastoma. Here we report on how RosettaDesign proteins are being used to treat brain cancer! It’s an amazing story.
Protein design holds tremendous promise for therapeutic application, and the Institute for Protein Design is closely tracking the progress of Rosetta designed proteins that enter clinical trials. One of these is a thermostabilized cytosine deaminase from yeast (Figure 1) that was initially developed for anticancer therapy by Dr. Margaret Black at Washington State University, and then further engineered for improved stability and activity by Aaron Korkegian (now working at IDRI) during his PhD studies in the laboratory of Dr. Barry Stoddard at FHCRC, a long time collaborator of Dr. David Baker’s group at the University of Washington.
Figure 1. PDBID:1YSB Structure of the yeast cytidine deaminase (yCD), triple mutant (Ala23Leu, Ile140Leu, Val108Ile magenta). The enzyme is a homo-dimeric (cyan and green) enzyme, requiring Zn++ for its active site function (grey spheres)
Now ~8 years later, the code for a protein with features like the thermostabilized Rosetta designed yCD has been incorporated into a novel retroviral gene therapy replicating vector, “Toca 511”, by San Diego based Tocagen, Inc. who are testing it in an innovative clinical trial to help stop the tumors in brain cancer patients. The way it works is kind of tricky, and like most cancer treatments, it was first tried in mice with human tumor xenografts as reported here and here, and shown to have clear proof of concept before trying it in patients. Called pro-drug gene therapy (PGT), the treatment involves gene therapy encoding thermostabilized cytosine deaminase together with a pro-drug oral therapy that for cancer cells is “to die for” (Illustrated in Figure 2).”
Figure 2. Pro-drug gene therapy illustration.
Briefly, Toca 511 is injected into brain tumors where it instructs the cells to produce a triple mutant thermostabilized yeast cytosine deaminase protein similar to the one that the Stoddard, Baker and Black groups reported back in 2005. After allowing time for Toca 511 to spread through the tumor, each patient begins a course of an extended-release oral tablet containing 5-FC (5-fluorocytosine) a well-tolerated anti fungal agent serving as a pro-drug in this case. The Toca 511 enzyme converts the antifungal 5-FC into the potent anti-cancer drug 5-FU (5-fluorouracil), the active drug that is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase, which interferes with DNA replication, leading to cancer cell death.
This pro-drug activator gene therapy is offering hope for patients, and according to Tocagen staff, it has been used in the treatment of over 50 people thus far. We at the Institute for Protein Design wish Tocagen and the brain cancer patients all the best of outcomes!
This article was Authored by Dr. Lance Stewart, Sr. Director of Strategy (email@example.com) at the Institute for Protein Design, with kind input and guidance from the researchers noted in this article, along with Tocagen representative Dr. Douglas Jolly, and with the aid of web resources linked throughout this posting.
September 16, 2013
September 16, 2013
The Life Sciences Discovery Fund (LSDF) today announced its latest round of Opportunity Grants, and awarded $1.4 M to the University of Washington (UW) to support translational development and commercialization of medically useful designer proteins discovered at the Institute for Protein Design (IPD) in the laboratory of principal investigator Dr. David Baker, the Head of the IPD (Figure 1). The LSDF funding is to be matched by contributions from UW and private donors (donations which can be made here).
LSDF IPD UW Opportunity Grant Award 9-16-13
Figure #1. Protein designs shown here represent self-assembling nano-particle protein cages that can be used for drug delivery (left), an designed enzyme called KumaMax that is the basis for an oral celiac disease therapy (middle), and a protein designed to bind the cardiac glycoside small molecule digoxigenin (right).
Dr. David Baker commented “The Institute for Protein Design is generating whole new classes of designer proteins with broad application to vaccines, diagnostics and therapeutics. We greatly appreciate the tremendous vote of confidence that LSDF has given the IPD, in making this LSDF Opportunity Grant award to support the commercial translation of these assets.”
Entitled “Launch of the Institute for Protein Design for Creating New Therapeutics, Vaccines and Diagnostics,” this LSDF Opportunity Grant Award will enable the IPD to translate protein design discoveries and projects into commercially viable products in collaboration with the Center for Commercialization (C4C) entrepreneurs in residence, the Arthur W. Buerk Center for Entrepreneurship in the Foster School of Business, and the Institute of Translational Health Sciences (Figure 2).
“These Opportunity grants, to two of our state’s top research institutions, will help Washington maintain its leadership position in cancer research and treatment and capitalize upon the outputs of some of our most innovative and productive investigators,” noted LSDF board chair Carol Dahl.
Figure #2 With LSDF funding and matching support from philanthropists, the Institute for Protein Design will be able to convert V1.0 protein designs (Seeds) into V4.0 enhanced versions that have commercial viability (Sprouts) that can be the asset basis for new company formation (Spin Outs). This will be done with the support of C4C, Foster School, ITHS, and other Washington state resources.
Translation of IPD’s Designer Proteins from Seed to Sprout to Spin-Out
Commercialization track record
The IPD has already spawned five spinout companies, disclosed 37 inventions (12 since 2011), applied for 55 patents with six issued to date, and issued 27 commercial and nearly 10,000 academic Rosetta licenses in 94 countries. In addition, ~360,000 Rosetta@home participants who donate idle computer time and ~330,000 registered Foldit (a free protein-folding game) players are helping work out the three-dimensional profile of proteins to accelerate the time from discovery to product.
The power of private support
The LSDF seeks to leverage its investments with significant matching contributions from philanthropic donations which can be made here. Private support will be critical in building the IPD. Investments from visionary philanthropists will have an impact in donors’ lifetimes, while serving as a legacy for future generations of researchers, physicians and patients. You can also help us by installing Rosetta@home to put your idle computer to use for protein design, or by playing Foldit where you and other gamers are cracking important protein folding challenges.
For more information
For more information on the UW Institute for Protein Design, please contact Andrew Welch, Assistant Vice President at UW Medicine Advancement, at 206-616-6464 or firstname.lastname@example.org. Thank you for your interest in our work.
This article was Authored by Dr. Lance Stewart, Sr. Director of Strategy (email@example.com) at the Institute for Protein Design, with kind input and guidance from UW colleagues, and with the aid of web resources linked throughout this posting.
September 4, 2013
September 4, 2013
Digoxigenin binding protein (ribbon) bound to digoxigenin (stick); Illustration prepared by Vikram Mulligan
Reported on-line in Nature (Sept. 4, 2013) researchers at the Institute for Protein Design describe the use of Rosetta computer algorithms to push the envelope on protein design; crafting a protein that binds with high affinity and specificity to a small drug molecule. More information can be found here, and here.
Usually drug hunters are doing the exact opposite; designing small molecules to bind to large protein targets. Proteins are the workhorses of life, and most drugs used today are small molecules that block protein function. For example, the cocktail drug therapies used to treat HIV infection are made of a mix of small molecules which individually block important viral replication proteins, and together they do a good job of shutting down the virus. From aspirin to penicillin, small molecule drugs work by binding with specificity to a limited number of cellular protein targets, where they inhibit protein activity; like throwing a wrench in a gearbox.
Now, researchers at the Institute for Protein Design have inverted the drug design principle, by designing completely novel proteins that bind to small drug molecules.
As reported in the paper entitled “Computational design of ligand-binding proteins with high affinity and selectivity,” Dr. Christine Tinberg and a team of scientists working in Dr. David Baker’s group at the University of Washington, have designed a new protein to bind the cardiac glycoside digoxigenin, a natural steroid component of digitalis found in the flowers of foxglove plants, and often given to cardiac patients with atrial fibrillation or heart failure. This is the first report of computer-designed proteins that recognize and bind with high affinity to small molecules.
Their Nature paper is accompanied by a News & Views commentary, “Computational biology: A recipe for ligand binding proteins.” The commentator, Giovanna Ghirlanda of Arizona State University, wrote that the method developed “to design proteins with desired recognition sites could be revolutionary” because cell processes such as cell cross-talk, the production of gene products and the work of enzymes all depend on molecular recognition.
The University of Washington’s news channel ran a story “Pico-world dragnets: Computer-designed proteins recognize and bind small molecules.” Science ran a commentary entitled “Protein Designers Go Small.” The story even made news at Slashdot.
Why is this important?
Small molecules such as drugs, vitamins, scents, flavors, and pheromones are ubiquitous participants in biological processes, pharmaceuticals, and personal care products. Molecular recognition of these compounds is a critical first step in designing novel diagnostics and therapeutics. A reliable pipeline of designed proteins with cavities that bind small molecules with exquisite specificity (e.g. digoxigenin binding sensor) will enable at-home diagnostic testing for disease state biomarkers; and such proteins may also serve as therapeutic sponges for toxic small molecules. More importantly however, this proof of concept allows the IPD to confidently pursue potentially many more lucrative applications for proteins designed to bind small molecule targets. These include diagnostics for nutrient deficiency, and quantification or therapeutic sequestration of drugs with narrow therapeutic indices requiring careful dose control.
A protein designed to bind the cardiac glycoside, digoxigenin, a natural small molecule drug derived from the foxglove plant
The image here is a 3D printed model of the digoxigenin binding protein (red with yellow small molecule) was prepared by the Open3DP lab in the Department of Mechanical Engineering at UW (special thanks to Brandon Bowman, Dr. Mark Ganter, and Dr. Duane Storti for their 3D printing expertise).
This article was Authored by Dr. Lance Stewart, Sr. Director of Strategy (firstname.lastname@example.org) at the Institute for Protein Design, with kind input and guidance from the researchers noted in this posting, and information from web resources linked throughout this posting.
November 8, 2012
Scientists at the IPD describe a set of “rules” for the design of proteins from scratch in the latest issue of Nature.
Proteins are an enormous molecular achievement: chains of amino acids that fold spontaneously into a precise conformation, time after time, optimized by evolution for their particular function. Yet given the exponential number of contortions possible for any chain of amino acids, dictating a sequence that will fold into a predictable structure has been a daunting task.
Now researchers report that they can do just that. By following a set of rules described in a paper published in Nature today1, a team from David Baker’s laboratory at the University of Washington in Seattle has designed five proteins from scratch that fold reliably into predicted conformations. In a blind test, the team showed that the synthesized proteins closely match the predicted structures.
One might wonder how designing a new protein from scratch could be better than starting with natural proteins, given the head start that nature has in evolving effective functions and stable conformations. In fact, evolution has honed the structures of many proteins so precisely that it can be difficult to get the backbone to budge into another conformation to accommodate a new function, Baker says. “This paper provides the opportunity to design the structure and function at the same time,” says Baker. “Rather than taking an already existing scaffold, now you can design a backbone to order for exactly the function you want to carry out.” That will be the next step — incorporating function into the designs.
Read the full article here.
September 4, 2012
The Institute for Protein Design and David Baker’s laboratory move into the new Molecular Engineering & Sciences building located in the heart of the University of Washington campus. Read about the Institute’s new home and its exciting research in the Seattle Times.
The four-story, $77 million Molecular Engineering & Sciences building opened this month, just south of Gerberding Hall. And unlike old labs of the past, which tended to be dark and isolating, this one is filled with sunlight and designed with collaborative spaces for scientists to work together across a range of disciplines….
…Biochemistry professor David Baker gestured to researchers lined up in a row of desks, working on computers to design proteins that could help treat Ebola, Hodgkins Lymphoma and AIDS.
Baker said the most promising discoveries are licensed to private companies to carry on the research and find out if the proteins really do what researchers thought they would do. “We do simple things, then license the results to a pharmaceutical company,” he said.
Of those 400 proteins being investigated each month, about 25 to 50 a month are inspired by an unusual source: Online gamers playing Foldit, a free protein-folding game (www.fold.it), that was developed in collaboration between the UW’s molecular biology department and the UW’s Center for Game Science, Baker said.
About 230,000 players worldwide have downloaded the game, and use intuition and spatial reasoning to try to design proteins with stable, efficient designs.
Another contribution to unraveling protein structures comes from the more than 300,000 people who have downloaded a UW-designed program — Rosetta@home — which works kind of like a screen saver, taking advantage of processing time on idle computers. It, too, tries to work out the three-dimensional profile of proteins.