WRF Innovation Fellows Program
The Institute for Protein Design is fortunate to be situated in Seattle with a wealth of expertise in healthcare, medicine, computer science, materials science, and engineering. With a generous gift from the Washington Research Foundation (WRF), the IPD has launched the WRF Innovation Fellows Program supporting research partnerships between the IPD and other Seattle-area research institutes or UW departments.
We are not accepting new applications at this time.
HUA BAI, PhD – Collaborating PI: David Galas, Pacific Northwest Diabetes Research Institute
To restore auto-antigen tolerance in autoimmune disease models, especially in Type 1 Diabetes model, Hua will work under the guidance of Dr. David Galas at the Pacific Northwest Diabetes Research Institute and Dr. David Baker at the Institute for Protein Design to design and validate therapeutic peptides (or small proteins) that can interfere with the auto-antigen*MHC*T-cells complex, and hence inhibit the activation of pathogenic T-cells. On the other hand, by exploiting self-assembling nanoparticles design methods, Hua will design tolerogenic MHC*peptide complexes which can promote the proliferation of regulatory T cells and then induce auto-antigen tolerance. This project can potentially create novel tolerogenic therapeutics, and it can lead to a better understanding of immune tolerance mechanisms as well.
Hua obtained a B.S. degree in Biological Sciences in Peking University, China. Later, he came to the University of Wisconsin-Madison pursuing a Ph.D. degree in physiology. After two years of working on “metabolism” using animal models and five years of studying “membrane trafficking”using various in vitro biochemistry and biophysics techniques, Hua’s career objective to be an outstanding protein engineer is getting clearer and more determined. Hua will be dedicated to addressing the metabolic syndrome and related disorders by utilizing the powerful protein design and engineering methods.
RALPH CACHO, PhD – Collaborating PI: Michael Gelb, Department of Chemistry
The anticancer agents salinosporamide A and rebeccamycin, the antifungal griseofulvin and the antibiotic vancomycin all contain carbon-halogen bonds. The presence of the halogen atom in these compounds is
vital to the activity of the respective molecules. A lack of specificity and regioselectivity (a process that favors bond formation at a particular atom) has hampered classical synthetic chemistry methods for carbon-halogen bond formation. But enzymes evolved a variety of elegant mechanisms to catalyze this synthetically challenging reaction. Hence novel methods for the introduction of carbon-halogen bonds in advanced synthetic or biosynthetic intermediate with complex molecular scaffolds can be developed by engineering these halogenating enzymes.
My project aims to apply computational protein design to redesign a chlorinase enzyme with a modified substrate scope. To demonstrate the potential of computational protein design to efficiently change the substrate scope of the enzyme, I will design the chlorinase to catalyze the conversion of dechlorogriseofulvin to griseofulvin. Griseofulvin is an antifungal compound used in the treatment of skin and scalp infections caused by dermatophytes like tinea capitis and tinea pedis. While previous engineering approaches have been performed on chlorinase enzymes, previous examples use indole-containing substrates (such as tryptamine) or aryl rings with nitrogen substituents (such anthranilic acid or kyneurine). While these examples highlight the plasticity of the substrate scopes of this class of enzymes, they also highlight the deficiencies of the current approaches used to modify the specificity of flavin-dependent chlorinases. My project aims to supplement these current methods with computational design by targeting a reaction involved in the synthesis of a medically relevant compound.
QIAN CONG, PhD – Collaborating PI: Harmit Malik, Fred Hutchinson Cancer Research Center
Similarities between biological systems are frequently the result of descent from the common ancestor, and variations modulate the properties without disrupting shared functionalities. The centerpiece of biological enquiry, the function, is a consequence of interactions between molecules, cells and organisms. Interactions in an evolvable system are shaped by coevolution at all levels, within and between organisms. Imprints of coevolution can be deciphered by the analysis of co-variation in large datasets and used to predict functional interactions, suggest hypotheses for experimentation, and streamline discovery process.
My research program will focus on coevolution in biological systems and harvesting coevolutionary information from large genomic datasets to predict functional properties. First, I will develop computational methods to deduce interactions between proteins, model spatial structures of macromolecular complexes and apply them to medically important systems. Next, I will analyze coevolution at the level of cells and organisms to address the question about genetic determinants of host-pathogen specificity. Finally, I will use coevolutionary considerations to study epistasis and complex traits with the emphasis on non-monogenic diseases.
I graduated from Peking University in Biological Sciences and got my Ph. D. in Molecular Biophysics from the University of Texas Southwestern Medical Center in Dallas, TX. I studied the evolution of protein structures, developed methods to assess structure prediction and to facilitate protein sequence analysis, and applied these methods to proteins related to disease. Furthermore, I established experimental and computational pipelines to sequence, assemble, annotate and comparatively analyze eukaryotic genomes using butterflies as model organisms. Broad training in protein bioinformatics and genomics allows me to use integrative approaches that combine knowledge- and data-based computation with experimental validation.
TIMOTHY CRAVEN, PhD – Collaborating PI: Jay Shendure, UW Genome Sciences
As a WRF fellow Tim will be working with Jay Shendure (UW Genomics) and David Baker (UW Biochemistry and IPD) to engineer new methods to design synthesize repeat protein architectures and materials of biomedical interest.
Timothy started his scientific career with an emphasis on physical chemistry and obtained a B.Sc. form the College of New Jersey double majoring in Physics and Chemistry. After research stints at the National Aeronautics and Space Administration and the National Institutes of Standards and Technology Tim decided to switch scientific fields and pursue a M.Sc. in Bioinformatics at Georgetown University. After graduating Georgetown and a short research stint at the Food and Drug Administration Tim moved to New York University and completed a PhD in Biology with an emphasis on computational design and synthesis of biomimetic molecular architectures co-advised between the labs of Richard Bonneau (NYU Biology) and Kent Kirshenabum (NYU Chemistry).
KRISTINE DEIBLER, PhD – Collaborating with Dr. Philip Greenberg, Fred Hutchinson Cancer Research Center
The goal of Kris’s research is to design novel selective peptide-small molecule binders. Peptide binders possess similar advantages compared to proteins and small molecules since they offer specificity by providing greater contact via tertiary structure while also being smaller and more stable.
In particular, she will be working with Prof. David Baker at the University of Washington (de novo design expertise) and Dr. Philip Greenberg at the Fred Hutchinson Cancer Research Center (immunology expertise) to design selective peptide-small molecule binders for specific inhibition of protein tyrosine phosphatases (PTPs) in the context of cancer immunotherapy treatment. Ultimately this will provide access to tools that will allow us to study the unique roles of two similar PTPs (SHP-1/2). Both are potential cancer therapeutic targets via two varying pathways.
Kris graduated with a Bachelor of Science in biochemistry from Duquesne University in Pittsburgh, PA. There she worked on the synthesis and design of heavy metal fluorescent ion sensors in the laboratory of Prof. Partha Basu. She then completed her PhD in chemistry in the laboratory of Prof. Karl Scheidt at Northwestern University. She was awarded the NSF graduate fellowship in 2014. During her doctoral research she developed chemical approaches for studying kinases selectivity, that lead to the development of selective kinase inhibitors for studying chemical pathways.
HUGH HADDOX, PhD
Advances in computational biology have enabled the field to design proteins with desired structures and functions completely from scratch. As described in the research summaries of other WRF fellows, this technology can be used to tackle a wide variety of challenges ranging from treating cancer to synthesizing biomaterials. However, doing so faces an obstacle: the success rate of protein design is still low, such that designs often fail to take on desired structures and functions when tested in the lab, requiring many to be tested before finding a hit. A major reason for this low success rate is that our models of the physical forces that shape proteins (e.g., van der Waals interactions, hydrogen bonds, etc.) are still imperfect. The goal of my project is to increase the success rate of protein design by increasing the physical accuracy of these models. The Baker lab recently developed a method for measuring the stabilities of thousands of protein designs in a single high-throughput experiment, allowing us to enumerate which designs successfully folded (stable) and which did not (unstable) for an unprecedentedly large number of proteins. I plan to optimize current design models by using such experimental data to retrain them. Specifically, I will first design thousands of proteins tailored to be highly informative for model optimization. Next, I will experimentally quantify each design’s stability. Finally, I will retrain the models to optimally predict these data. I expect the retraining to greatly improve the success rate of protein design, greatly accelerating our ability to use this technology to solve a wide variety of challenges in science and technology.
LUKE HELGESON, PhD – Collaborating PI: Trisha Davis, UW Biochemistry
The kinetochore is a ~100 protein molecular machine that connects microtubule ends to chromosomes and harnesses the power of depolymerizing microtubules to segregate chromosomes during cell division. Kinetochores must maintain their connection to chromosomes and microtubule ends while under high tension for a weakening of these connections can halt cell division or promote incorrect chromosome segregation. The kinetochore components that bind microtubules are mostly determined but it is unclear how multiple copies and the structural arrangement of these components can strengthen kinetochore microtubule attachments. Testing the microtubule end attachment strength of kinetochore components at specific binding geometries and stoichiometries will help determine how these attachments bear the forces necessary to regulate and perform chromosome segregation.
As a WRF fellow, Luke will carry out a research plan to test the microtubule end attachment strength of designed kinetochore protein particles. Luke will work with Dr. David Baker (UW Biochemistry and IPD) and Dr. Trisha Davis (UW Biochemistry) to design different protein domains with oligomeric states that are spatially and numerically controlled. These designed protein domains will be attached to kinetochore proteins and purified to yield single particles of kinetochore components at known stoichiometries and geometries. The microtubule end attachment strength of the engineered particles will be tested using optical tweezers microscopy through collaboration with Dr. Charles Asbury (UW Physiology and Biophysics). By using protein design, Luke will be able to directly test how the structure of kinetochore components bound to microtubule ends can modulate the force bearing capabilities of the kinetochore.
Luke graduated with a Bachelor of Science in biochemistry from Iowa State University; where he helped to solve the structure of an Ebola virus protein in the laboratory of Dr. Gaya Amarasinghe. For his graduate work, Luke studied under Dr. Brad Nolen at the University of Oregon. In the Nolen lab, Luke developed single-molecule microscopy experiments to understand how branched actin networks are nucleated and architecturally regulated. For his postdoctoral training, Luke joined the laboratory of Dr. Trisha Davis at the University of Washington where he plans to further his knowledge of cytoskeleton biology and single-molecule microscopy.
Thaddaus Huber, PhD – Collaborating PI: Jesse Bloom, Fred Hutchinson Cancer Research Center
Creation of a universal flu vaccine that can result in lasting resistance to multiple strains of influenza as well as newly emerging strains is of extraordinary interest. Thaddaus will work under the guidance of Dr. Neil King at the Institute for Protein Design and Jesse Bloom at Fred Hutchinson Cancer Research Center to develop two-component protein nanoparticles displaying flu antigens to induce broadly neutralizing antibodies (bNAbs).
Thaddaus completed his PhD in Chemical and Biological Engineering in the laboratory of Dr. Christopher Snow at Colorado State University. During his doctoral research he developed methods to use a highly porous protein crystal for scaffold assisted crystallography of guest molecules. He is excited for his new opportunity to further develop expertise in protein design and learn cutting-edge methods such as cryo-EM.
Gyu Rie Lee, PhD – Collaborating PI: Dustin Maly, UW Chemistry
The goal of Gyu Rie’s research is to develop new computational methods for designing proteins which specifically bind to assigned small molecules. She is mostly interested in incorporating ligand flexibility and protein dynamics in binder design. She hopes to increase the efficiency and efficacy of the computational work, which will allow large-scale design of small molecule-binding proteins.
Particularly, as a WRF fellow, Gyu Rie will develop a method for designing a protein switch, which selectively binds to ABL kinase in its ligand-bound state. She will pursue this by working jointly with Dr. David Baker and Dr. Dustin Maly. Molecular switches are developed to sense external signals and regulate the activity of the targeting system. A protein switch which targets ABL kinase bound to its small molecule inhibitor, Gleevec, will be designed in this study. Kinases have multiple binding sites and it has been found that the activity can be controlled more selectively when these sites are targeted together. Gyu Rie will design a switch that targets the secondary binding site of the ABL kinase by considering the conformational change upon ligand binding. The developed molecular switch will be able to control the signaling pathway via ABL kinase. Also, it can be applied to generate a system, which induces dimerization of fusion proteins each linked to the designed protein and the ABL kinase.
Gyu Rie obtained a B.Sc. at Seoul National University majoring in Chemistry Education and minoring in Biological Sciences. She got her Ph.D. in Physical Chemistry also at Seoul National University by doing her graduate studies in the lab of Dr. Chaok Seok. The research she carried out in Dr. Seok’s lab was focused on developing computational methods for refining predicted protein structure models. The developed methods were successfully tested on refinement categories held by recent Critical Assessment of protein Structure Prediction experiments. By studying protein structures, Gyu Rie became more interested in predicting the functions of proteins using the models. She extended her refinement method to predict the ligand-bound G protein-coupled receptor complex structures.
Shiri Levy, PhD. Collaborating PI: Hannele Ruohola-Baker, Biochemistry Department.
Direct reprogramming of the epigenome has tremendous potential to advance applications in disease modeling, drug discovery, and gene and cell therapies. Specifically, histone modifications in promoters and enhancers genes possess distinct features in gain and loss of function. A good example for wide epigenetic repressive marks is in human Embryonic Stem Cells (hESC), as massive gene silencing takes place in early development prior to differentiation. Precise manipulation of histone modification in promoter and / or enhancer areas can therefore lead to cellular reprograming, and encode for lineage specific cell fate.
Together with the Institute of Protein Design (IPD), we apply computational protein design to engineer synthetic, novel proteins that mimic epigenetic modifiers. In order to achieve precise gene target in promoter and /or enhancer areas we incorporate the newly designed proteins with CRISPR-associated null Cas9 nuclease (dCas9). Our goal is to create the ability to reprogram control of gene expression or repression using newly designed epigenetic modifiers while targeting any genomic locus of interest through the simple exchange of the 20-nt targeting sequence of the guide RNA (gRNA). Thus, this technology launches new platform for reprogrammable cell linages as well as introducing control of developmental plasticity of hESC that is largely governed by specific nucleosome architecture.
Shiri received her bachelor’s degree in molecular and cellular biology from the University of Washington in Seattle. After receiving her master’s degree in molecular biology and biochemistry, Shiri focused her graduate studies in exploring the control of gene expression in human mitochondria under the supervision of Prof. Gadi Schuster at the Technion, Israel Institute of Technology. During her PhD studies, Shiri characterized a family of orphan proteins that responsible for digestions of RNA and DNA in both ancient archaea and human mitochondria.
RUBUL MOUT, PhD – Collaborating PI: Jim De Yoreo, Pacific Northwest National Laboratory
As a WRF Innovation Fellow at the Institute for Protein Design (IPD), Rubul will work with Prof. David Baker (at IPD) in collaboration with Dr. James J De Yoreo (Pacific Northwest National Laboratory, PNNL). Rubul aims to rebuild some of the large cellular protein machineries, completely from the scratch (de novo), using computational and experimental methods. In one such endeavor, he aims to build a nanodisc-like structure by hierarchically organizing oligomeric protein complexes. Such nanodisc-like protein assemblies are prevalent in many cellular machineries such as immunological synapse, apoptosomes, inflammasomes, and in bacteriorhodopsins, to name a few. He then hopes to use these protein machineries in various applications for remodeling immunological synapse for cancer immunotherapy, intracellular protein networks, and in optogenetics to understand our brain functions. He also aims to build globular protein assembly to mimic/reengineer cellular proteasomes which may be useful to treat neurodegenerative diseases such as Parkinson’s disease.
Rubul was born and grew up in a farmer family in a remote village in the North-East of India. After receiving M.Sc. degree in Chemistry from Gauhati University, Assam, India, he researched at the Tata Institute of Fundamental Research, Mumbai in the field of malarial parasite immunology. He then moved to the University of Massachusetts Amherst to pursue his PhD under Prof. Vincent M. Rotello at the Department of Chemistry. At UMASS, he invented a technology that allowed delivering proteins directly into cell cytosol. This technique was later used to transduce a variety of proteins into mammalian cells including CRISPR/Cas9 systems for gene editing.
Rubul is also the author of two books in his native Assamese language: a collection of short stories and a memoir.
GRETCHEN PRITCHARD, PhD
Malaria, caused by infection with Plasmodium parasites, is a major global health burden. B cell expressed antibodies are critical for protective immunity against malaria yet little is known about Plasmodium-specific B cells. Recent studies from the Pepper laboratory have revealed functional heterogeneity among high affinity memory B cells (MBCs) responding to Plasmodium. Remarkably, somatically hypermuated IgM MBCs respond faster to a secondary infection than classically defined IgG MBCs. For the first aim of this project, the signals that lead to the generation of these distinct MBC populations will be elucidated. These studies will inform the second aim of the project, which is to design and engineer immunomodulatory nanoparticles (NPs) in order to drive specific MBC populations. These highly modular NPs are unique as they can be rapidly assembled and are very stable. NPs will express Plasmodium antigens in the context of additional immunomodulatory molecules to induce specific populations of Plasmodium-specific MBCs in mice. The NPs will also be modified to express antigens from Plasmodium species that infect humans in order produce a novel, effective malaria vaccine. These groundbreaking studies have the potential to impact vaccine design to many diseases including HIV and tuberculosis.
After graduating from Oberlin College, Gretchen volunteered as a science teacher in the Peace Corps in Malawi and then worked as a research technician in Dr. Yongwon Choi’s laboratory at the University of Pennsylvania. She then stayed at the University of Pennsylvania where she earned a PhD in Immunology. Under the mentorship of Dr. Christopher Hunter, she examined the role of the Th1-inducing transcription factor T-bet during the immune response to the intracellular parasite Toxoplasma gondii, and uncovered novel functions of this transcription factor.
ANINDYA ROY, PhD – Collaborating PI: David Rawling, Seattle Children’s/UW Immunology
As a WRF fellow, Anindya will be working with Dr. David Rawlings (Seattle Children’s Hospital) and Dr. David Baker (UW Biochemistry and IPD) to develop APRIL and BAFF specific inhibitors for the development of therapeutics for autoimmune diseases and cancer. Both these ligands have been shown to play critical roles in maintaining humoral immunity and signaling network pertaining to this ligand axis is highly exploited in cancer and autoimmune diseases. Current therapeutic approach relies on utilizing the soluble extracellular domain of the receptor for these ligands to block the signaling network. However, initial clinical trial results show that extracellular receptor decoy might not be a safe therapeutic agent presumably due to the complexity and shared ligand space of this signaling network under normal conditions. This project under the WRF fellowship aims to design orthogonal binding partner for BAFF and APRIL with high affinity and specificity.
Anindya started his scientific career with a special interest in chemical biology and protein biochemistry. He received his MSc from the Indian Institute of Technology (IIT-Kharagpur, India) studying protein-small molecule interactions using biophysical techniques. In 2008, Anindya moved to the US and received his PhD from Arizona State University under the guidance of Dr. Giovanna Ghirlanda where he worked on de novo design of artificial metalloproteins. In this work, he laid the foundation for designing multi-cofactor redox proteins that go beyond naturally existing systems.
DANNY SAHTOE, PhD – Collaborating PI: Andrew Scharenberg, Seattle Children’s Research Institute
Plant pathogens cause significant economic damage since they often inject toxic small molecules and proteins into the cells of agriculturally important plants, such as tomato and bean plants, that can lead to crop loss. One of such pathogens is the bacterium Pseudomonas syringae. In his project*, Danny’s aim will be to introduce novel proteins, that are designed to bind and neutralize a subset of Pseudomonas syringaetoxins, into plant cells in order to protect plants from such pathogens. The genetic accessibility of plants and the long standing GMO tradition in plant biotechnology, makes plants suitable candidates for computational protein design approaches. We hope that in the future, our designer proteins will complement the strategies that are currently used to combat plant disease in agriculture.
Danny obtained his PhD in structural biology and biochemistry in Titia Sixma’s lab at the Netherlands Cancer Institute in Amsterdam, the Netherlands. There he worked on elucidating the regulatory mechanisms of a special class of proteases called deubiquitinating enzymes using X-ray crystallography and a variety of biochemical and biophysical techniques.
*Danny Sahtoe is an EMBO long term fellow and was also awarded a WRF innovation fellowship that supports his non-salary research expenses.
TYLER STARR, PhD – Collaborating PI:
Antibodies mediate immunity to viruses and other pathogens by binding to specific antigenic targets. Our bodies deploy an evolvable arsenal of naïve antibodies capable of responding to diverse antigens. Upon exposure to a new antigen, potent and mature antibodies emerge from this arsenal through the Darwinian process of affinity maturation, consisting of iterative rounds of mutation and selection for improved binding to the antigen. This work seeks to understand the underlying relationship between sequence and function that guides this somatic evolutionary process, by combining antibody lineage reconstruction, high-throughput mutational scanning, and structural modeling approaches. This framework will be applied to an important class of HIV-targeting antibodies that are the subject of ongoing efforts in vaccine design and antiviral therapy.
Tyler obtained a BA in Biology and Biochemistry from Willamette University in Salem, Oregon, where he conducted research with Dr. Chris Smith on the iconic Joshua trees of the Mojave Desert. He combined his interests in evolutionary biology and protein biochemistry during his PhD in Biochemistry and Molecular Biophysics with Dr. Joe Thornton at the University of Chicago, where he used ancestral sequence reconstruction and high-throughput mutational scanning to understand the ancient evolution of protein functions. He seeks to apply this framework, previously used on proteins that existed more than 500 million years ago, to the proteins that evolve in our own bodies over the course of weeks and years during an immune response.
This week we report the design of new proteins that cluster antibodies into dense particles, rendering them more effective. In laboratory testing, such clustered antibodies neutralize COVID-19 pseudovirus, enhance cell signaling, and promote the growth of T cells more effectively than do free antibodies. This new method for enhancing antibody… Read more
Scientists at the IPD and Ovchinnikov lab at Harvard have applied deep learning to the challenge of protein design, yielding a new way to quickly create protein sequences that fold up as desired. This breakthrough has broad implications for the development of protein-based medicines and vaccines. Computational protein design has… Read more
The field of protein structure prediction has greatly advanced in recent years thanks to increasingly accurate deep-learning methods. A new such method, called trRosetta developed at the Institute for Protein Design, has now made thousands of protein structures available via EMBL-EBI’s Pfam and InterPro data resource. More than 6300 protein structures have been predicted… Read more
Biochemists have created barrel-shaped proteins that embed into lipid membranes, expanding the bioengineering toolkit. In a milestone for biomolecular design, a team of scientists has succeeded in creating new proteins that adopt one of the most complex folds known to molecular biology. These designer proteins were shown in the lab… Read more
Washington Research Foundation (WRF) has provided a $250,000 grant to support work carried out by Stephanie Berger, Ph.D., on a new therapeutic for patients with inflammatory bowel disease (IBD). A grant of $50,500 from WRF in 2019 and an award from Washington Entrepreneurial Research Evaluation and Commercialization Hub (WE-REACH) in 2020 enabled Berger,… Read more
This week we report [PDF] a new way to detect the virus that causes COVID-19, as well as antibodies against it. Scientists at the Institute for Protein Design have created protein-based sensors that glow when mixed with components of the virus or specific antibodies. This breakthrough could enable faster and more… Read more