Faculty Mentors

Assistant Professor of Chemical Engineering and of Genetics

The Abu-Remaileh Lab is interested in identifying novel pathways that enable cellular and organismal adaptation to metabolic stress and changes in environmental conditions. We also study how these pathways go awry in human diseases such as cancer, neurodegeneration and metabolic syndrome, in order to engineer new therapeutic modalities. To address these questions, our lab uses a multidisciplinary approach to study the biochemical functions of the lysosome in vitro and in vivo. Lysosomes are membrane-bound compartments that degrade macromolecules and clear damaged organelles to enable cellular adaptation to various metabolic states. Lysosomal function is critical for organismal homeostasis—mutations in genes encoding lysosomal proteins cause severe human disorders known as lysosomal storage diseases, and lysosome dysfunction is implicated in age-associated diseases including cancer, neurodegeneration and metabolic syndrome. By developing novel tools and harnessing the power of metabolomics, proteomics and functional genomics, our lab will define 1) how the lysosome communicates with other cellular compartments to fulfill the metabolic demands of the cell under various metabolic states, 2) and how its dysfunction leads to rare and common human diseases. Using insights from our research, we will engineer novel therapies to modulate the pathways that govern human disease.

Kenneth Fong Professor and Professor of Bioengineering, of Genetics, of Medicine, of Biomedical Data Science, Senior Fellow at the Stanford Institute for HAI and Professor, by courtesy, of Computer Science

I am interested in the application of computational technologies to problems in molecular biology of relevance to medicine. In particular, my laboratory focuses on drug response at the molecular level, working in three areas. First, we are building a comprehensive pharmacogenomics knowledge base (http://www.pharmgkb.org/) that provides access to information relating genotype to phenotype (in particular, how variation in genetics leads to variation in response to drugs). We are interested in collaboratively discovering and applying new pharmacogenomics knowledge. Second, we are interested in the analysis of three dimensional biological structures. We have methods for analyzing protein structures to recognize and annotate active sites and binding sites, particularly in the context of interactions with small molecule drugs. We are also interested in physics-based simulation of biological structures to understand how their dynamics impact their function (http://simbios.stanford.edu/). Finally, we are interested in computational methods for analyzing functional genomics information. We use natural language processing techniques for extracting and summarizing information in the literature, chemoinformatics methods for understanding small molecule function, and machine learning & data mining techniques to understand the molecular responses to drugs.

Associate Dean, School of Medicine, Roger and Joelle Burnell Professor of Genomics and Precision Health, Professor of Medicine (Cardiovascular Medicine), of Genetics, of Biomedical Data Science and, by courtesy, of Pathology

The Ashley lab is focused on precision medicine. We develop methods for the interpretation of whole genome sequencing data to improve diagnosis of genetic disease and to personalize the practice of medicine. We love big data questions and systems approaches to biology especially analysis of network graphs. The wet bench is where we test causality of key genes and investigate the biology of network modules. It is also the focus of our translational efforts. Therapeutic development is a near term goal and several of our discoveries are the focus of patents or are being actively pursued by pharmaceutical and biotechnology partners.

Catharine and Howard Avery Professor of the School of Medicine and Professor of Genetics

The observations that the p53 gene is mutated in at least half of all human cancers of a wide variety of types and that p53 null mice develop cancer at 100% frequency together underscore the critical role for p53 in tumor suppression. Wild-type p53 is a cellular stress sensor, responding to diverse insults such as DNA damage, hyperproliferative signals, and hypoxia by inducing growth arrest or apoptosis, responses thought to be important to tumor suppression. At the molecular level, p53 acts a transcription factor that activates gene expression programs to induce these different responses. Interestingly, in its capacity as a cellular stress sensor, p53 also plays physiological roles beyond tumor suppression as well as causing certain pathological effects. For example, p53 plays beneficial roles such as promoting fertility, and can promote detrimental phenotypes in certain situations such as the side effects of cancer therapies or developmental diseases. The overarching goal of our research is to better define the mechanisms by which the p53 protein promotes different responses in different settings, ranging from tumor suppression to responses to chemotherapeutics, using the mouse as an in vivo model system, with the ultimate goal of gaining insight that may facilitate clinical advances in diagnosis, prognostication and therapy. We utilize a combination of mouse genetic, cell biological, biochemical, and genomic approaches to address understand how p53 acts mechanistically. We hope to decipher the transcriptional networks responsible for mediating p53 functions in different contexts, an understanding that will help us understand how to best promote the beneficial and minimize the detrimental effects of p53 in the clinic.

We have a number of specific areas of investigation, which include:

  • Defining the transcriptional networks responsible for tumor suppression, using CRISPR/Cas9 and shRNA high-throughput genetic screening approaches
  • Identifying p53-interacting partners by mass spectrometry approaches
  • Elucidating the genes activated and repressed by p53 in diverse settings using genomic technologies such as ChIP-sequencing and RNA-sequencing, to understand how p53 drives different responses
  • Identifying p53 inhibitors to find strategies to suppress the detrimental effects of p53 activation, such as during cancer therapy
  • Understanding p53’s role in developmental diseases such as CHARGE syndrome
  • Characterizing p53-regulated noncoding RNAs and their roles in cancer
  • Examining mechanisms of p53 gain-of-function properties in cancer

We examine how cells communicate and function during fetal development. The work in my laboratory focuses on the establishment of specific cell fates using genomics to decipher interactions between chromatin and developmental signaling cascades, between genomes and rapidly evolving cell types, and between genomic copy number variation and gene expression. In recent years we have focused on the vastly understudied biology of the trophoblast lineage, particularly how this lineage evolved.

Associate Professor of Genetics

Our lab studies how intricate control of gene expression and cell signaling is regulated on a minute-by-minute basis to give rise to the remarkable diversity of cell types and tissue morphology that form the living blueprints of developing organisms. Work in the Barna lab is presently split into two main research efforts. The first is investigating ribosome-mediated control of gene expression genome-wide in space and time during cellular differentiation and organismal development. This research is opening a new field of study in which we apply sophisticated mass spectrometry, computational biology, genomics, and developmental genetics, to characterize a ribosome code to gene expression. Our research has shown that not all of the millions of ribosomes within a cell are the same and that ribosome heterogeneity can diversify how genomes are translated into proteomes. In particular, we seek to address whether fundamental aspects of gene regulation are controlled by ribosomes harboring a unique activity or composition that are tuned to translating specific transcripts by virtue of RNA regulatory elements embedded within their 5’UTRs. The second research effort is centered on employing state-of-the-art live cell imaging to visualize cell signaling and cellular control of organogenesis. This research has led to the realization of a novel means of cell-cell communication dependent on a dense network of actin-based cellular extension within developing organs that interconnect and facilitate the precise transmission of molecular information between cells. We apply and create bioengineering tools to manipulate such cellular interactions and signaling in-vivo.

Associate Professor of Genetics

Endocytic Pathogens as Tools and Targets

Endocytic pathogens such as protein aggregates, viruses, protein toxins, and bacteria have evolved remarkable ways to enter the cell, disrupt homeostasis, and cause cell death. We use these agents both as probes to understand normal cellular trafficking and signaling events, and to find key targets for therapy.

Stress Signaling to the Cell Death Machinery

Cells have elaborate mechanisms of sensing diverse stresses (oxidative damage, nutrient deprivation, DNA breaks, etc), and must either repair damage or induce cell death. Misregulation of these pathways results in diseases such as cancer and Alzheimer’s. We would like to understand how these signals connect to the death pathway in health and disease in order to improve therapies.

Technology Development and Genetic Interaction Maps

Customized genome-scale gene perturbation libraries: Much of the work we do utilizes genetic screens enabled by novel high-coverage CRISPR/Cas9 libraries (10 sgRNAs/gene) and shRNA libraries (25 shRNAs/gene) we have developed. The high coverage greatly reduces false positive and false negative results. Our platform allows for easy creation of new library designs, and we use a pooled format that can be used to rapidly screen genome-scale libraries in ~1-2 weeks. Libraries can then be analyzed by deep sequencing to quantify changes in sgRNA/shRNA abundance.

Systematic comparison of gene perturbation technologies: We have systematically compared the ability of genome-wide RNAi and CRISPR/Cas9 deletion screens to identify drug targets and essential genes, and have found important differences in their outputs. For example, while both screens perform well in detecting a gold standard set of essential genes, they can identify distinct essential biological processes. Moreover, each technology exhibits its own set of off-target effects and limitations in on-target efficacy.

Using what we have learned about these technologies, we recently created new genome-wide CRISPR libraries that incorporate a number of improved sgRNA features and controls. With a novel statistical framework (casTLE) we can model on- and off-target effects accurately, markedly improve hit detection, and even combine results from screens to improve performance and further limit false positives and false negatives. These studies have demonstrated the utility of parallel screening approaches using complementary technologies to reveal a more complete biological picture.

Systematic genetic interaction maps: We have also developed strategies to systematically knock down/knock out pairs of genes. This has facilitated some of the first systematic genetic interaction maps in mammalian cells. Using these maps, we can understand coordinated gene functions and predict new functions for uncharacterized genes. They also allow us to quickly identify synergistic interactions under stress conditions that we hope to exploit for combination therapies.

Directed evolution using dCas9-targeted somatic hypermutation (CRISPR-X): More recently, we developed a strategy to re-purpose the somatic hypermutation machinery used in antibody diversification to create targeted populations of point mutations. Using dCas9 to recruit a hyperactive variant of the deaminase AID, we can target diverse point mutations within an ~100bp window centered on the sgRNA PAM site. These mutant populations can then be subjected to selection to evolve proteins with improved function or to map the sites of drug-protein interactions. For example, by tiling mutations across PSMB5, we could map known and novel mutations that affect binding to the chemotherapeutic bortezomib.

Associate Professor of Medicine (Hematology) and of Genetics

Our lab seeks to exhaustively characterize the dynamics of the microbiome in patients with noncommunicable diseases (cancer, cardiometabolic disease), and to explore how changes in the microbiome are associated with clinical outcomes in this population.

Our Lab's Goals and Objectives:
a) We strive to better understand what microbial genes do, and how these genes are regulated
b) We hope to understand if shifts in the microbiome are associated with human disease phenotypes.
c) If alterations in the microbiome are associated with human disease phenotypes, develop methods to modify the composition of the microbiome or target specific microbial gene products with the hope of ameliorating these disease phenotypes.

Assistant Professor of Developmental Biology

My research aims to improve our understanding of how cells with the same genome can develop dramatically different behaviors. For example, consider the mechanical abilities of a muscle cell compared to the electrical excitability of a neuron, or the industrious activity of bone building cells in a youthful person compared to an elderly one. Each of these cells, (if taken from the same individual) has an identical genome — and yet each is “reading” a very distinct subset of that genome and consequently carrying out very different behaviors. The choice of what to read and what to hide away is made during development. An increasing body of data suggests this is accomplished by modifying the genome both in the nature of the proteins bound to different sequences and in the spatial organization of those sequences relative to each other. The spatial organization or folding of the genome may be particularly important in complex multicellular organisms, since many of the sequences known to interact based on genetic data are nonetheless substantially separated from each other along the linear genome. By regulating the folding of this linear sequence into a higher order structure, a cell might change which regulatory sequences have access to which genes, and achieve different behavioral states.

So far we have little imaging data on how the genome is folded within a cell on the length scale of individual genes, or whether this folding is regulated in any way relevant to the behavior of the cell. Our limited knowledge stems largely from want of a method that has both the resolution and specificity to visualize such genomic substructure. Conventional fluorescent microscopy has developed excellent tools for coloring specific regions of DNA and particular DNA-associated proteins with uniquely colored dyes — but lacks the resolution to turn these colored blurs into structures. Electron-microscopy has substantially greater resolution but lacks compatibility with specific labeling techniques to tell different gene clusters or different protein types apart. Super-resolution imaging approaches promise to address this balance by allowing the use of fluorescent labels while simultaneously resolving structures on the nano-scale. I have been adapting this approach to uncover the nano-scale structure of chromatin and determine to how this structure changes when bound by different types of nuclear proteins. While individual gene clusters appear as quite diverse structures, there appear to be a few general features, for example, linking structure with the epigenetic state.

Michele and Timothy Barakett Endowed Professor

The overarching goal of our lab is to understand the genetic mechanisms of aging and longevity. Aging is a highly plastic process regulated by a combination of genetic and environmental factors.

We have a long-standing interest in the genetic pathway that connects insulin to FOXO transcription factors, a central pathway to regulate lifespan from worms to humans. We use a combination of genetic, molecular, and cellular approaches to analyze the regulation and importance of FOXO transcription factors, and more generally 'longevity genes' in mammals. We are particularly interested in the role of longevity genes in the maintenance of the pool of adult neural stem cells and intact cognitive function during aging. We also use ultra-high throughput sequencing technologies to study epigenetic changes and transcriptional networks during aging.

In parallel, our goal is to identify novel ‘longevity genes’ using short-lived animal models. Our lab uses unbiased approaches in the nematode C. elegans to identify novel pathways that control organismal longevity, particularly in response to dietary restriction. We are particularly interested in the role of chromatin modifiers in the regulation of lifespan and metabolism.

Finally, we are developing the extremely short-lived African killifish N. furzeri as a new vertebrate model for aging studies. We are taking advantage of this fish to explore the genetic architecture of longevity in vertebrates.

Professor of Molecular and Cellular Physiology, of Neurology, of Photon Science and, by courtesy, of Structural Biology

Nerve cells communicate by releasing the contents of neurotransmitter-bearing synaptic vesicles into the space between adjoining cells. This process depends on a handful of proteins that promote vesicle and nerve cell membrane fusion. The Brunger lab team uses structural and biophysical tools to capture this machinery at different stages of vesicle fusion. These structures (Figure 1) then provide the framework for further investigations, using microscopy and live neurons, into the functional and dynamic aspects of the system.

SNARE proteins, found in both nerve cell and vesicle membranes, set the stage for fusion by zipping together into a parallel, four-helix bundle that juxtaposes the two membranes. Brunger and his collaborators determined the first x-ray crystal structure of the neuronal SNARE complex, as well as the structures of other key components of the synaptic release machinery. Recently, the Brunger’s team visualized the SNARE complex bound to the Ca2+-sensor synaptotagmin-1 and to the regulator complexin, revealing two interfaces that are essential for fast synchronous release of neurotransmitters. The structure of this three-part complex suggests that it is in a primed and locked state. Action-potential-driven Ca2+ ions bind to the synaptotagmin proteins, unlock the complex, and trigger membrane fusion on a sub-millisecond timescale.

After fusion has occurred, SNARE complexes are recycled by the ATPase NSF, which breaks down the SNARE complex into its individual components. The Brunger team visualized this molecular machine at near-atomic level and obtained the first glimpses of how this SNARE-recycling machine works. The SNARE complex resembles a rope with a left-handed twist, and NSF uses adapter proteins called SNAPs to grasp the “rope” in multiple places. The SNAPs wrap around the SNARE complex with a right-handed twist, suggesting that the disassembly occurs via a simple unwinding motion that frees the zipped SNARE proteins.

The Brunger team is also using structural and functional studies to explore other machinery relevant to neurotransmitter release, such as factors involved in priming and pre-synaptic plasticity. Their research may one day provide new possibilities for targeting therapeutics to control neurotransmitter release.

Adjunct Professor, Biomedical Data Science

My genetics research focuses on analyzing genome wide patterns of variation within and between species to address fundamental questions in biology, anthropology, and medicine. We focus on novel methods development for complex disease genetics and risk prediction in multi-ethnic settings. I am also interested in clinical data science and development of new diagnostics.I am also interested in disruptive innovation for healthcare including modeling long-term risk shifts and novel payment models.

Virginia and D. K. Ludwig Professor of Cancer Research and Professor of Genetics

The same genetic blueprint gives rise to thousands of cell types that make up the human body. Intricate mechanisms govern the choice to make skin, heart, or brain cells. These different cell types must be correctly arranged in spatial patterns to make functioning tissues and organs. In many organisms with continual turnover of cells, the genome faces the additional challenge of ensuring the faithful transmission of information throughout a lifetime-over decades in the case of humans. Thus, how one genome encodes thousands of patterns in space and time is of central importance to biology and medicine. Inappropriate activation of genes can give rise to birth defects, premature aging, or cancer, among many other diseases. Restoration of proper organ function often requires restoring homeostatic gene regulation.

Long Noncoding RNAs and Positional Identity
As a practicing dermatologist, I am fascinated by what makes human skin from different parts of the body different, a fact that guides the diagnosis and treatment of many skin diseases. Why do long hairs grow on the scalp but not on our palms or soles? How do cells know where they are located in the body, and how do they remember this information?

We discovered that one class of skin cells, the fibroblasts, encode the positional identity of skin via specific markings on their chromatin, the DNA-protein complex where genes reside. Based on the chromatin configurations of specific genes, most notably the HOX genes, fibroblasts differentially activate hundreds of genes based on their the cells location along three anatomic axes- anterior-posterior (head to tail), proximal-distal (close or far away from the trunk), and dermal-nondermal (surface or internal organ). This in effect creates a global positioning system for all cells to navigate.

These studies also revealed a surprising abundance of long intergenic long noncoding RNAs (also known as lincRNAs, a newly recognized type of genes that do not code forencode proteins) that are involved in programming chromatin states. We are particularly fascinated by HOTAIR, the first known lincRNA that can regulate the chromatin state of genes on distantly located chromosomes. We now appreciate that the genome is pervasively transcribed to give rise to thousands of lincRNAs, which are likely to play key roles in the gene regulation of diverse biological states and disease. We are interested in understanding how lincRNAs control gene activity, and in deciphering the rules that will allow the functions of thousands of lincRNAs to be predicted and studied.

Large-Scale Gene Regulatory Programs in Cancer Metastasis and Self-Renewal
In contrast to the orderly acquisition of positional identity, cancer progression is characterized by abrogation of normal positional boundaries, especially in metastasis, which is the leading cause of cancer death. We and many others have previously identified gene expression signatures (GES ), composed of dozens to hundreds of genes, that distinguish indolent human cancers from those prone to metastasis; these signatures can provide improved prognostic prediction for cancer patients. Furthermore, we have developed methods to pinpoint master regulators of GES singular control points that can toggle the activity of the entire genetic program. This allows complex gene programs observed in human cancers to be easily recapitulated in the laboratory as models for drug development. This has enabled the creation of faithful laboratory models of human cancer types, identified specific drugs that can target these cancers, and revealed the hierarchy of transcriptional programs involved in the generation of cancer stem cells the cells that continually repopulate a tumor or its metastases.

Assistant Professor of Pathology (Pathology Research) and of Genetics

Dr. Cong's research group at the Department of Pathology and Department of Genetics is developing technology for genome editing and single-cell genomics, using computational approaches inspired by data science. His group has a focus on using these tools to study immunological and infectious diseases. His work has led to one of the first FDA-approved clinical trials employing viral delivery of CRISPR/Cas9 gene-editing for in vivo gene therapy. More recently, his group has invited high-efficiency tools for large-scale genome engineering based on novel microbial proteins, and developed single-cell analysis approach with applications in cancer biology and immunology. Dr. Cong is a recipient of the NIH/NHGRI Genomic Innovator Award, a Baxter Foundation Faculty Scholar, and has been selected by Clarivate Web of Science as a Highly Cited Researcher.

RZ Cao Professor, Professor of Genetics and of Biomedical Data Science

We are particularly interested in elucidating tumor evolutionary dynamics, novel therapeutic targets, and the genotype to phenotype map in cancer. A unifying theme of our research is to exploit ‘omic’ data derived from clinically annotated samples in robust computational frameworks coupled with iterative experimental validation in order to advance our understanding of cancer systems biology. In particular, we employ advanced genomic techniques, computational and mathematical modeling, and powerful model systems in order to:

  1. Model the evolutionary dynamics of tumor progression and therapeutic resistance and metastasis
  2. Elucidate disease etiology and novel molecular targets through integrative analyses of high-throughput omic data
  3. Develop techniques for the systems-level interpretation of genotype-phenotype associations in cancer

Our research is funded by the NIH/NCI, NHGRI, Department of Defense, Breast Cancer Research Foundation, American Association for Cancer Research, Susan G. Komen Foundation, Emerson Collective and V Foundation for Cancer Research.

Professor of Biochemistry and of Genetics

We are using Saccharomyces cerevisiae and Human to conduct whole genome analysis projects. The yeast genome sequence has approximately 6,000 genes. We have made a set of haploid and diploid strains (21,000) containing a complete deletion of each gene. In order to facilitate whole genome analysis each deletion is molecularly tagged with a unique 20-mer DNA sequence. This sequence acts as a molecular bar code and makes it easy to identify the presence of each deletion. The mixture of all such tag strains then allows for the analysis of the entire genome with the manipulation of a single culture. During growth under a variety of conditions the loss of a tag indicates the loss of a deletion from the population. The concentration of each tag is determined by PCR amplification of the tags and hybridization to an Affymetrix DNA chip that contains the complement to all of the DNA sequence tags. This approach is being applied to other microorganisms.

We have identified a number of wild isolates of yeast that grow at much higher temperatures than is typical for Saccharomyces cerevisiae and are pathogenic and can kill a mouse. Microarrays have been used to map complex genetic traits such as virulence traits in pathogenic Saccharomyces cerevisiae using hybridization to detect single nucleotide polymorphisms. We have developed a new technology termed Reciprocal Hemizygosity Scanning that allows the determination of the contribution to the phenotype of all pair wise alleles for the whole genome from 2 independent strains. Using this technology we can map and quantitate all of the alleles in the genome for any complex quantitative trait in a single tube assay. These technologies will allow us to explore allelic contributions in complex mixed culture real environments and to investigate ecology at the genome level.

We are conducting a whole genome analysis (transcriptome and proteome) from blood of Human trauma patients. In this large clinical study we are establishing the standards for clinical genomics. We have developed 2 new technologies, "Molecular Inversion Probes" (MIP) for massive multiplex analysis of SNP and DNA content in Human and, "Mismatch Repair Detection" for discovery of rare Human polymorphisms. Both technologies are being applied to numerous clinical investigations.

Assistant Professor of Genetics

Jesse is an Assistant Professor at Stanford University in the Department of Genetics and the Children’s Heart Center Basic Sciences and Engineering (BASE) Initiative. The Engreitz Lab aims to map the regulatory wiring of the genome to understand the genetic basis of heart diseases. Previously, Jesse was currently a Junior Fellow at the Harvard Society of Fellows and the Broad Institute, where he developed large-scale CRISPR tools to map enhancer-gene regulation, and launched the Variants-to-Function (V2F) Initiative to connect genetic disease variants to their molecular and cellular functions. Jesse completed his PhD in the Harvard-MIT Division of Health Sciences and Technology, where he studied long noncoding RNAs with Eric Lander and Mitch Guttman.

Burnet C. and Mildred Finley Wohlford Professor

Human genetic and cultural evolution, mathematical biology, demography of China

George D. Smith Professor of Molecular and Genetic Medicine and Professor of Pathology and of Genetics

Our lab studies the mechanisms by which cells and organisms respond to genetic change.

The genetic landscape faced by a living cell is constantly changing. Developmental transitions, environmental shifts, and pathogenic invasions lend a dynamic character to both the genome and its activity pattern.We study a variety of natural mechanisms that are utilized by cells adapting to genetic change. These include mechanisms activated during normal development and systems for detecting and responding to foreign or unwanted genetic activity. At the root of these studies are questions of how a cell can distinguish "self" versus "nonself" and "wanted" versus "unwanted" gene expression.

We primarily make use of the nematode C. elegans in our experimental studies. C. elegans is small, easily cultured, and can readily be made to accept foreign DNA or RNA. The results of such experiments have outlined a number of concerted responses that recognize (and in most cases work to silence) the foreign nucleic acid. One such mechanism ("RNAi") responds to double stranded character in RNA: either as introduced experimentally into the organism or as produced from foreign DNA that has not undergone selection to avoid a dsRNA response. Much of the current effort in the lab is directed toward a molecular understanding of the RNAi machinery and its roles in the cell. RNAi is not the only cellular defense against unwanted nucleic acid, and substantial current effort in the lab is also directed at identification of other triggers and mechanisms used in recognition and response to foreign information.

Professor of Medicine (Oncology) and of Genetics and, by courtesy, of Pediatrics

The major investigative focus of this laboratory and translational research program is to explore the mammalian genetic determinants of the inducible response and cellular sensitivity to DNA damage, focusing particularly on the effects of the p53 and BRCA1 gene products on DNA repair and cancer susceptibility. We have found that loss of p53 and BRCA1 function results in defective repair of DNA damage, including effects on homologous recombination, nucleotide and base-excision repair. In addition, we are exploring ways to exploit the DNA repair deficiency of p53 and BRCA1 mutant cancer cells and to identify targeted therapeutic approaches for the treatment and prevention of related cancers.

Role of BRCA1 in base-excision DNA repair (BER): BRCA1 appears to have complex regulatory effects on multiple DNA repair pathways in addition to their shared role in homologous-recombination and DNA double strand break repair. We first described that breast cancer cell lines mutant for the BRCA1 gene exhibit sensitivity to oxidative DNA damage. We also developed a novel viral based “host-cell reactivation” assay to measure the repair of oxidative DNA damage in living cells using an adenoviral GFP reporter gene, and demonstrated that BRCA1 mutant cells were defective in BER.

Discovery of small molecules that activate BER and may prevent BRCA1-associated tumors: We designed and performed a high-throughput screen to identify small-molecules that enhance DNA repair in a BRCA1 mutant background, and thus may serve as candidate agents for prevention of cancer by enhancing DNA repair and interrupting multistep mutagenesis. Several of these drugs are potentially “repurposeable” and are currently or were previously used in humans for other indications. We have shown activity of two in preventing the development of BRCA1-associated breast cancers in mice and are developing plans for a clinical trial using the lead hit for prevention of BRCA1-associated premalignant changes in ovaries from women undergoing risk-reducing bilateral oopherectomies.

Clinical translation of Next-Generation Sequencing for hereditary cancer risk assessment: We recently led the first clinical study of next-generation gene panel DNA sequencing among women referred for breast cancer risk assessment using germline DNA samples from our large translational research biobank containing more than 2000 specimens, all donated by individuals tested for BRCA1/2 or other gene mutations. We found that >10% of patients had potentially pathogenic mutations in genes other than BRCA1/2, thus doubling the rate of identified germline cancer susceptibility gene alterations in this population, a discovery that has enabled early detection of cancers.

Targeting TNBC and other malignancies with DNA damaging drugs and PARP: We found through preclinical studies and clinical trials that nearly all BRCA mutation associated breast cancer, and approximately half of non-BRCA mutant TNBC exhibit clinical sensitivity to platinum chemotherapy and synthetic lethality with PARP inhibitors. As part of these efforts, we performed extensive correlative studies on tumor tissue and germline DNA samples obtained from patients enrolled in a large, multi-institutional neoadjuvant clinical trial, using gene expression microarrays, DNA copy-number analyses, and germline DNA sequencing. We described a bioinformatic measure of homologous recombination deficiency (HRD) that is highly predictive of clinical response in these patients. Our current and future research goals in this area is to leverage our expertise in germline and tumor genomics to identify patients with breast and other cancers harboring DNA repair gene defects and HRD for treatment using PARP inhibitors and other DNA repair directed therapies (ATR and DNA-PK inhibitors). We have also developed breast cancer cell lines resistant to PARP-inhibitors and are exploring the mechanism for this drug resistance.

Associate Professor of Bioengineering and of Genetics

Cellular function and organismal homeostasis are governed by molecular interactions. Protein-DNA binding interactions are essential for regulating gene transcription and translation, dense networks of protein-protein and protein-peptide interactions further regulate cellular function, and enzymes make possible all of the chemical transformations essential to metabolism and signaling. Our goal is to understand, and eventually engineer, these complex processes by building and testing biophysical models of how the molecules that drive these processes work. To do so, an essential first step is to obtain the necessary quantitative measurements of the fundamental kinetic and thermodynamic constants of these molecular interactions and catalytic processes—the “universal language” needed to describe and ultimately predict function. In our lab, we use microfluidics and extensive hardware automation to perform these quantitative measurements at an unprecedented scale via 3 main platforms:

1. Array-based multiplexing experiments (MITOMI and HT-MEK) employ microfluidic devices containing 1,568 valved reaction chambers aligned to printed DNA arrays. We are currently using these devices to better understand how transcription factors find and bind their genomic targets to regulate gene expression, as well as to understand how enzymes achieve their extraordinary catalytic efficiency and substrate specificity.

2. MRBLEs (Microspheres with Ratiometric Barcode Lanthanide Encoding) rely on spectral multiplexing to track analytes throughout an experiment. We can create microspheres containing > 1,000 distinct ratios of lanthanide nanophosphors that can be uniquely identified via imaging alone, and are now using these MRBLEs in a variety of downstream assays.

3. Dropception is a microfluidic platform for creating double emulsion (water-in-oil-in-water) droplets that can be sorted in high-throughput using standard flow cytometers (FACS machines). We recently demonstrated the ability to generate and sort double emulsion droplets without breakage, isolate individual rare droplets of interest in wells of a multiwell plate, and recover all encapsulated nucleic acids, enabling a wide range of novel single-cell multi-omic techniques.

Professor of Biology

We study the evolution of complex traits by developing new experimental and computational methods.

Our work brings together quantitative genetics, genomics, epigenetics, and evolutionary biology to achieve a deeper understanding of how genetic variation shapes the phenotypic diversity of life. Our main focus is on the evolution of gene expression, which is the primary fuel for natural selection. Our long-term goal is to be able to introduce complex traits into new species via genome editing.

Donald Kennedy Chair in the School of Humanities and Sciences and Professor of Genetics

The long term goal of our research is to understand how proteins fold in living cells. My lab uses a multidisciplinary approach to address fundamental questions about molecular chaperones, protein folding and degradation. In addition to basic mechanistic principles, we aim to define how impairment of cellular folding and quality control are linked to disease, including cancer and neurodegenerative diseases and examine whether reengineering chaperone networks can provide therapeutic strategies.

Reed-Hodgson Professor of Human Biology, Katharine Dexter McCormick and Stanley McCormick Memorial Professor and Professor of Genetics and of Obstetrics/Gynecology (Reproductive and Stem Cell Biology)

My laboratory uses the Drosophila male germ line as a model to investigate how self-renewal, proliferation and differentiation are regulated in adult stem cell lineages. The central characteristic of adult stem cells is their long-term capacity to divide as relatively undifferentiated precursors while also producing daughter cells that initiate differentiation. Understanding the mechanisms that regulate stem cell specification and the choice between stem cell self-renewal and differentiation is crucial for realizing the potential of stem cells for regenerative medicine. We are using the Drosophila male germ line as a powerful genetic system to identify both the cell autonomous determinants and the extrinsic cell-cell interactions that govern stem cell specification, self-renewal, and differentiation. One of the great advantages of this system is that stem cells can be studied in situ, in the context of their normal support cells. Our results indicate that signals from surrounding somatic support cells specify asymmetric division of male germ line stem cells by inducing one daughter cell to self-renew stem cell identity while directing the other daughter cell to differentiate. A second focus of our work concerns how the developmental program directs cellular differentiation. Fundamental cellular functions like the cell cycle, the cytoskeleton, and the general transcription machinery are remodeled during development to give rise to specialized cell types. Several lines of research in our laboratory have recently converged on the molecular mechanisms underlying the developmentally programmed switch from proliferation to differentiation, a key regulatory point in the adult stem cell lineages that underlie tissue maintenance and repair. Failure to cleanly execute this switch may contribute to genesis of cancer. Our results implicate a number of molecular and cellular mechanisms in regulating this critical switch. We find that RNA binding proteins involved in translational control and alternative splicing act cell autonomously to regulate the cessation of proliferation and that progression of differentiation requires communication from associated somatic support cells. We discovered that a developmentally regulated alternate choice of site at which certain nascent transcripts are cut to form 3’ ends, leading to production of novel mRNA isoforms with shortened 3’UTRs, controls dramatic changes in the suite of proteins expressed in differentiating spermatocytes compared to proliferating spermatogonia. We found that dramatic changes in chromatin open over 2000 new promoters with novel core sequence structure to turn on the new cell type specific transcription program when cells initiate spermatocyte differentiation. Some of the earliest genes turned on in this differentiation program encode chromatin associated proteins that prevent spurious opening of normally cryptic promoters, thus preventing massive misexpression of genes associated with the wrong cell type. Other transcripts upregulated with differentiation onset encode cell type-specific translational regulators that delay production of core G2/M cell cycle machinery to program the extended G2 phase of meiotic prophase. Our goal over the next 5 years is to map how these processes collaborate to form the regulatory circuitry that initiates then executes the switch from proliferation to differentiation.

Stanford Medicine Basic Science Professor

We use the baker’s yeast, Saccharomyces cerevisiae, as a model system to study the cell biology underpinning protein-misfolding diseases like Parkinson's disease and ALS. Since dealing with misfolded proteins is an ancient problem, we hypothesize that the mechanisms employed to cope with them are likely conserved from yeast to man. Our long-term goal is to identify the critical genes and cellular pathways affected by misfolded human disease proteins.

C9orf72 in ALS and FTD: Disease models and mechanisms

Mutations in the C9orf72 gene are the most common cause of ALS and frontotemporal dementia (FTD). The mutation is a massive hexanucleotide repeat (GGGGCC) expansion in the intron of C9orf72. The mechanism by which C9orf72 mutations cause disease has remained unclear and of intense interest. In collaboration with the Petrucelli laboratory we have recently identified a way to selectively inhibit the expression of both sense and antisense mutant C9orf72 transcripts, which could offer therapeutic potential (Kramer et al., Science 2016).

New yeast models of neurodegenerative diseases

Encouraged by the power of the yeast system to gain insight into α-synuclein biology, we are creating new yeast models to study additional protein-misfolding disorders, including Alzheimer’s disease and ALS. We recently developed a yeast model to study the ALS disease protein TDP-43 (Johnson et al., Proc Natl Acad Sci USA 2008).

We have used yeast and in vitro biochemistry (in collaboration with Jim Shorter at PENN) to analyze the effects of ALS-linked TDP-43 mutations on aggregation and toxicity (Johnson et al., J Biol Chem 2009). We are now using these models to perform high-throughput genetic and small molecule screens to elucidate the molecular pathways that regulate the function of these disease proteins and control their conversion to a pathological conformation. We are currently analyzing hits from recent high-throughput screens that identified potent modifiers of TDP-43 toxicity. We are validating these hits in cell culture, animal models (mouse, fly, and zebrafish), and human patient samples.

These TDP-43 modifier screens are providing insight in two main ways:

1. The genes and pathways that are able to modify TDP-43 toxicity in yeast are now good candidates for evaluation as genetic contributors to ALS and related disorders in humans (e.g., see ataxin 2 below).

2. The yeast hits and their homologs are candidate therapeutic targets, especially gene deletions (Armakola et al., Nat Genet 2012; Kim et al., Nat Genet 2014).

Ataxin-2 and ALS

Interestingly, one of the hits from our yeast TDP-43 genetic modifier screen, PBP1, is the homolog of a human neurodegenerative disease protein, ataxin 2. We have validated this genetic interaction in the fly nervous system (in collaboration with Nancy Bonini at PENN), used biochemistry to show the proteins physically associate in an RNA-dependent manner.

We analyzed the ataxin 2 gene in 915 individuals with ALS and 980 healthy controls and found mutations in this gene as a common geneticrisk factor for ALS in humans. Long polyglutamine (polyQ) expansions (>34Q) in ataxin 2 cause spinocerebellar ataxia type 2 (SCA2). We found intermediate-length polyQ expansions in ataxin 2 (27-33Q) significantly associated with increased risk for ALS (Elden et al., Nature 2010). A role for polyQ expansions in ataxin 2 in ALS and related diseases is being evaluated by us and others in independent patient populations worldwide. Click here for an updated summary of these results.

We found that lowering levels of ataxin 2 in mouse, either by knockout or with antisense oligonucleotides (ASOs) can markedly extend survival and reduce pathology in TDP-43 transgenic mice (Becker et al., Nature 2017). We are extending these studies to additional mouse models and testing effects of ataxin 2 lowering in human cell models.

Professor of Pediatrics (Endocrinology) and of Genetics

The consistent focus of Anna’s research has been using naturally occurring mutations in humans as tools to identity critical regulatory pathways and insights into normal physiology. Her early post-doctoral research led to the identification a new genetic aetiology for permanent and transient neonatal diabetes due to KCNJ11 mutations and resulted in one of the first examples of precision medicine, where the determination of the molecular genetic aetiology lead to improved treatment options for patients. Whilst in Oxford, Anna's team discovered a novel genetic cause of constitutive insulin sensitivity in humans due to mutations in the PTEN gene highlighting the complex interplay between pathways involved in cell-growth and metabolism.

Anna's current research projects are focused on the translation of genetic association signals for type 2 diabetes and glycaemic traits into cellular and molecular mechanisms for beta-cell dysfunction and diabetes. Her group uses a variety of complementary approaches, including human genetics, functional genomics, physiology and islet-biology to dissect out the molecular mechanisms driving disease pathogenesis.

Anna is an active member of multiple internal genetic discovery efforts including: NIH/Pharma funded Accelerated Medicines Partnership, DIAGRAM (Diabetes Genetics Replication and Meta-analysis), MAGIC (Meta-analysis of Glucose and Insulin traits Consortium), Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) and the Genetics of Type 2 Diabetes (GoT2D). She was also involved in the IMI funded STEMBANCC project which focused on delivering human IPS cell derived beta-cell models for drug discovery efforts.

Anna is also involved in several initiatives under the Human Islet Research Network (HIRN): the NIDDK funded Human Pancreas Atlas Programme (HPAP) for Type 2 Diabetes, and the Integrated Islet Phenotyping Programme (IIPP).

Deane F. and Kate Edelman Johnson Professor of Law and, Professor, by courtesy, of Genetics

My current interests in neuroscience involve the consequences of advances in neurosciences for 1) predicting future diseases or traits; 2) reading minds to allow detection of subjective mental states such as pain, recognition, bias, or memory; 3) "treating" non-disease traits; 4) cognitive enhancement; 5) detecting consciousness and handling issues around disorders of consciousness; and 6) issues of responsibility.

My current interests in human genetics focus on 1) prenatal genetic diagnosis, 2) the effects of widespread adoption of clinical whole genome sequencing, and 3) ethical, legal, and social issues in genomic biobanks.

In stem cell research, I am currently interested in 1) legal challenges to stem cell research and 2) issues around human/non-human chimeras.

My interests in human research protections, biological enhancement, and the future of reproduction draw on, and involve, all three of the substantive fields described above.

Our lab focuses on developing methods to probe both the structure and function of molecules encoded by the genome, as well as the physical compaction and folding of the genome itself. Our efforts are split between building new tools to leverage the power of high-throughput sequencing technologies and cutting-edge optical microscopies, and bringing these technologies to bear against basic biological questions by linking DNA sequence, structure, and function.