Dr Markita Landry
University of California, Berkeley
Department of Chemical and Biomolecular Engineering
Chan-Zuckerberg Biohub Investigator
landry@berkeley.edu
Markita Landry is an assistant professor in the department of Chemical and Biomolecular Engineering at the University of California, Berkeley. She received a B.S. in Chemistry and a B.A. in Physics from the University of North Carolina at Chapel Hill, a Ph.D. in Chemical Physics and a Certificate in Business Administration from the University of Illinois at Urbana-Champaign, and completed an NSF postdoctoral fellowship in Chemical Engineering at the Massachusetts Institute of Technology.
Her current research centers on the development of synthetic nanoparticle-polymer conjugates for imaging neuromodulation in the brain, and for the delivery of genetic materials into plants. The Landry lab exploits the highly tunable chemical and physical properties of nanomaterials for the creation of bio-mimetic structures, molecular imaging, and plant genome editing. She is also on the scientific advisory board of Terramera and on the scientific advisory board of Chi-Botanic. She is a recent recipient of over 20 early career awards, including awards from the Brain and Behavior Research Foundation, the Burroughs Wellcome Fund, the DARPA Young Investigator program, the Beckman Young Investigator program, the Howard Hughes Medical Institute, the NSF CAREER award, is a Sloan Research Fellow, an FFAR New Innovator, and is a Chan-Zuckerberg Biohub Investigator.
Imaging Brain Neuromodulators with Near-Infrared Fluorescent Nanosensors
Neurons communicate through neurotransmitter signals that either terminate at the postsynaptic process (“wired transmission”) or diffuse beyond the synaptic cleft to modulate the activity of larger neuronal networks (“volume transmission”). Molecules such as dopamine, serotonin, and neuropeptides such as oxytocin belong to the latter class of neurotransmitters, and have been the pharmacological targets of antidepressants and antipsychotics for decades. Owing to the central role of neuromodulators over a range of behaviors and psychiatric disorders, real-time imaging of the signal’s spatial propagation would constitute a valuable advance in neurochemical imaging. To this end, we present a library of nanoscale near-infrared fluorescent nanosensors for dopamine, serotonin, and oxytocin peptide, where the nanosensors are developed from polymers pinned to the surface of single wall carbon nanotubes (SWNT) in which the surface-adsorbed polymer is the recognition moiety and the carbon nanotube the fluorescence transduction element. Excitonic transitions in functionalized SWNT yield up to ΔF/F = 4500% near-infrared fluorescence emission in the presence of dopamine (Beyene et al. Nano Letters 2018), ΔF/F = 200% for serotonin (Jeong et al. Science Advances 2019), and ΔF/F = 120% for oxytocin (unpublished). We next demonstrate imaging of evoked dopamine and oxytocin release in acute brain slices, and show altered dopamine and oxytocin reuptake kinetics when brain tissue is exposed to dopamine receptor agonist and antagonist drugs (Beyene et al. Science Advances 2019). We characterize our findings in the context of their utility for high spatial and temporal neuromodulator imaging in the brain, describe nanosensor exciton behavior from a molecular dynamics (MD) perspective, and validate nanosensor for use to elucidate neuromodulator signaling variability with disease or pharmacological perturbations at a synaptic scale.
Dr Mohammed AlQuraishi
Mohammed AlQuraishi is an Assistant Professor in the Department of Systems Biology and a member of Columbia’s Program for Mathematical Genomics, where he works at the intersection of machine learning, biophysics, and systems biology. The AlQuraishi Lab focuses on two biological perspectives: the molecular and systems levels. On the molecular side, the lab develops machine learning models for predicting protein structure and function, protein-ligand interactions, and learned representations of proteins and proteomes. On the systems side, the lab applies these models in a proteome-wide fashion to investigate the organization, combinatorial logic, and computational paradigms of signal transduction networks, how these networks vary in human populations, and how they are dysregulated in human diseases, particularly cancer.
Dr. AlQuraishi holds undergraduate degrees in Biology, Computer Science, and Mathematics. He earned an M.S. in Statistics and a Ph.D. in Genetics from Stanford University. He subsequently joined the Systems Biology Department at Harvard Medical School as a Departmental Fellow and a Fellow in Systems Pharmacology, where he developed the first end-to-end differentiable model for learning protein structure from data. Prior to starting his academic career, Dr. AlQuraishi spent three years founding two startups in the mobile computing space.
Protein Structure Prediction in a Post-AlphaFold2 World
AlphaFold2 burst on the life sciences stage in late 2020 with the remarkable claim that protein structure prediction has been solved. In this talk I will argue that in some fundamental sense the core scientific problem of static structure prediction is finished, but that substantial further maturation is necessary before AlphaFold2 and similar systems can materially inform biological questions beyond those of structure determination itself. I will outline some of these necessary developments and highlight one in particular: the prediction of structure from individual protein sequences. I will describe present challenges and opportunities, and our efforts to tackle them by combining advances in protein language modeling with end-to-end differentiable structure prediction, presenting new results on the prediction of de novo designed proteins and proteins in the twilight zone of sequence space. Time permitting, I will end by speculating on what abundant availability of structural information might mean for the future of biology.
Dr Tony Hunter
Salk Institute for Biological Studies | Professor, Molecular and Cell Biology Laboratory
Renato Dulbecco Chair in Cancer Research; American Cancer Society Professor
Tony Hunter received his BA and PhD from the University of Cambridge, England, and completed postdoctoral training at the Salk Institute for Biological Studies and the University of Cambridge. In 1979, through his work on tumor viruses as a faculty member at the Salk Institute, he discovered a new class of protein kinases that phosphorylate tyrosine residues in proteins, and demonstrated that dysregulated tyrosine phosphorylation by an activated tyrosine kinase causes malignant transformation. Subsequently, he and others showed that tyrosine phosphorylation is a widespread reversible protein modification essential for the regulation of a wide variety of cellular processes in multicellular eukaryotes, including transmembrane signal transduction by surface receptors, cell growth control, cell migration, axonal guidance and neural transmission, and cell cycle control. His work together with that of many others has shown that aberrant tyrosine phosphorylation is causal in several types of human cancer and in other diseases, and this has led to the successful development of inhibitors that target disease-causing tyrosine kinases (TKIs), such as Gleevec, a BCR-ABL inhibitor used for treatment of chronic myelogenous leukemia. Currently, 54 TKIs are approved for clinical use in the treatment of cancer and other diseases.
Hunter has spent much of the past 40 years studying protein kinases and phosphatases, and the role of protein phosphorylation in cell proliferation and the cell cycle, and how aberrant phosphorylation causes cancer. His group also works on other types of post-translational modifications (PTMs), including ubiquitylation, where he discovered the RING domain class of E3 Ub ligases, and sumoylation, where he identified a class of E3 ubiquitin ligases, STUbLs, that specifically target sumoylated proteins for ubiquitylation. Most recently, he has been studying histidine phosphorylation, and has generated monoclonal antibodies specific for the two isoforms of phosphohistidine, and used these to uncover a role for histidine phosphorylation in liver cancer. Most recently, he has investigated the role of stromal cells in pancreatic cancer, discovering a role for the LIF cytokine secreted by cancer-associated fibroblasts in tumor progression.
Hunter has received many awards for his work on tyrosine phosphorylation, including a Gairdner Canada International Award, the Louisa Gross Horwitz Prize, the Wolf Prize in Medicine, the Royal Medal of the Royal Society, and most recently the Pezcoller-AACR Award for Cancer Research, the Sjöberg Prize for Cancer Research and the Tang Prize for Biopharmaceutical Science. He is a Fellow of the Royal Society of London and the American Association for Cancer Research Academy, and a Member of the US National Academy of Sciences, the European Molecular Biology Organization, the American Academy of Arts and Sciences, the US National Academy of Medicine, and the American Philosophical Society.
New Signal Transduction Targets for Cancer Therapy
Tyrosine phosphorylation of proteins was discovered over 40 years ago, and in the interim its fundamental importance in many human diseases, including cancer, has been revealed. Tyrosine kinases have proved to be viable cancer drug targets, and, to date, 54 tyrosine kinase inhibitors (TKIs) have been approved for clinical use, mostly as cancer therapeutics.
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with few treatment options. Using mass spectrometry (MS) approaches, we have identified leukemia inhibitory factor (LIF), a stem cell factor, as a key paracrine factor, secreted mainly by activated cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), that acts on pancreatic tumor cells to stimulate JAK tyrosine kinase-mediated STAT3 tyrosine phosphorylation, which drives a gene expression program that maintains a stem cell-like population of tumor cells. Blockade of LIF with a neutralizing monoclonal antibody (mAb) slows tumor progression in the KPC mouse model of PDAC and augments the efficacy of gemcitabine chemotherapy treatment to prolong survival. LIF levels are strongly elevated in both mouse and human pancreatic tumor tissue, and LIF is also detected in serum from tumor-bearing mice and human PDAC patients, suggesting its use as both as a biomarker and as a therapeutic target. In addition, to its action on tumor cells, we have found that LIF acts on myeloid cells in the immune microenvironment to sustain a protumorigenic population of tumor-associated macrophages.
Histidine phosphorylation, the so-called “hidden phosphoproteome”, is poorly characterized. To study histidine phosphorylation we generated mAbs that selectively recognize the 1-pHis and 3-pHis isoforms, and have determined the structural basis of selective antibody recognition of 1-pHis and 3-pHis in proteins. We have used these mAbs for immunoblotting and immunofluorescence staining to detect increased levels of pHis proteins in human cell lines, and also to survey the pHis proteome, and, using MS, to identify new sites of histidine phosphorylation. Using these mAbs, we collaborated with Michael Hall (Biozentrum, Basel) to show that pHis levels are elevated in liver tumors both in a mouse model and in human hepatocellular carcinoma (HCC) tumor tissue, as a result of reduced levels of the LHPP pHis phosphatase in tumor tissue. On this basis, we propose that LHPP serves as a tumor suppressor in HCC, and that histidine phosphorylation can act as a cancer driver. Consistently, we have recently observed elevated levels of pHis proteins in pediatric neuroblastoma and PDAC stromal cells.
Dr Daniela Grabs
Daniela Grabs has over 20 years of experience in the protein engineering field. Getting her career started working on catalytic antibodies with Prof. Don Hilvert at the ETH Zurich and learning phage display in Prof. Andreas Plückthun’s lab, she co-founded Arzeda after a post-doc in computational enzyme design with Prof. David Baker at the University of Washington/Seattle. At Arzeda, Daniela is responsible for all operational aspects on the experimental platform side.
Computational Enzyme Design in Industry
Engineering enzymes for an industrial target entails unique challenges: searching an immense sequence space for target reactions that are not easily amenable to traditional high-throughput screening while the enzyme needs to meet strict sequence, stability and activity criteria. With the help of a couple of case studies I will illustrate how computational enzyme design is ideally suited to provide enzyme solutions that improve performance and lift supply chain & cost-of-manufacturing constraints.
Dr Frank Sicheri
Frank Sicheri’s research interests center on understanding the structure and function of eukaryotic protein kinases and ubiquitin ligases. His lab uses structure-investigational tools to visualize the mechanisms that allow protein kinases and ubiquitin ligases to turn on and off in response to specific stimuli and to select specific substrates. As the dysregulation of protein kinases and ubiquitin ligases has been implicated in numerous human diseases, and as both enzyme classes have been validated as tractable drug targets, this provides the impetus for ongoing studies into how the two enzyme families’ function.
Frank obtained his Ph.D. in Dr. Daniel Yang’s laboratory at McMaster University where he received training in the application of X-ray crystallography to study the structure and function of anti-freeze proteins. He obtained post-doctorate training in Dr. John Kuriyan’s lab at the Rockefeller University where he applied X-ray crystallography and biochemistry to uncover how the multi domain protein kinase Src is regulated through the formation of an intricate higher order structure.
In 1998 he joined the Lunenfeld-Tanenbaum Research Institute at Sinai Health System as an independent investigator. He has appointments to the Departments of Molecular Genetics and Biochemistry at the University of Toronto.
Frank Sicheri holds a Canada Research Chair in protein kinase structural biology, an Apotex Chair in Molecular Oncology and is a Fellow of the Royal Society of Canada. Frank is a co-founder of MDS-proteomics and Repare Therapeutics and works closely with Pharma/Biotech partners to probe the structural basis for drug action.
Exploring the inner workings of the tRNA-modifying complex KEOPS
The tRNA modifying KEOPS complex, which is conserved across archaea and eukaryotes, is composed of four core subunits; Pcc1, Kae1, Bud32 and Cgi121. KEOPS is crucial for the fitness of all organisms. In humans, pathogenic mutations in KEOPS genes lead to Galloway-Mowat syndrome, an autosomal-recessive disease that results in childhood death. The Kae1 subunit of KEOPS catalyzes the universal and essential tRNA modification N6-threonylcarbamoyl adenosine (t6A), but the precise roles of the other KEOPS subunits remain an enigma. Using structure-guided studies we show that Cgi121 functions to recruit tRNA to KEOPS by binding to its 3'CCA tail. A composite model of KEOPS bound to tRNA reveals that all KEOPS subunits form an extended tRNA-binding surface, which has been validated in vitro and in vivo to mediate the interaction and modification of tRNA substrate. These findings provide a framework for understanding the inner workings of KEOPS and delineate why all KEOPS subunits are essential for life.
