PRISM Mentors

Maya Mathur is an Assistant Professor at the Stanford University Quantitative Sciences Unit and the Associate Director of the Stanford Center for Open and Reproducible Science. She is a statistician whose methodological research focuses on advancing methods for meta-analysis, replication studies, and sensitivity analysis. She has received early-career and young investigator awards from the Society for Epidemiologic Research, the Society for Research Synthesis Methods, and American Statistical Association.

Our laboratory is developing tools to study genetic variants commonly found in Asians within the basic science laboratory including CRISPR mouse models, drug development/design, and protein chemistry. Most of our laboratory uses basic science techniques to study the cardiovascular system and we are funded through the NIH from NIGMS and NHLBI. Our NIGMS funded project focuses on genetic variants in Asians and developing precision medicine strategies for reducing perioperative organ injury and precision medicine strategies for delivering anesthesia and pain relievers such as opioids. Our NHLBI funded project is to study the cardiopulmonary effects of e-cigarettes in rodents and to further determine how a common genetic variant in East Asians may impact the cellular toxicity of e-cigarettes.

Chronic pain affects 1 in 3 Americans at a huge cost to society. A more thorough understanding of the basic mechanisms contributing to chronic pain is crucial to the development of therapies that target the likely unique underlying causes of diverse pain conditions. Projects in the Tawfik Lab use clinically-informed basic science approaches to further understand the crosstalk between the nervous system and the immune system in several mouse models of perioperative injury. In particular, we have an interest in CNS glial cells (astrocytes and microglia) which, after injury, can contribute to central sensitization and persistence of pain. Preclinical use of glial modulators has been successful at reversing existing pain, however, translational efforts have thus far failed. We strive to further understand glial subtypes and functional phenotypes in order to better tailor glial-directed therapies. Our projects involve collaborations with several other labs in Neurology, Radiology and Anesthesiology in a collegial environment focused on rigorous science and close mentorship.

To understand biology, we need chemistry and physics as the physical and chemical properties of biomolecules enable and constrain what biology can do and how it has evolved. We are particularly interested in questions of: (i) how enzymes work; (ii) how RNA folds; (iii) how proteins recognize RNA; (iv) RNA/protein interactions in regulation and control; and (v) the evolution of molecules and molecular interactions. Our interdisciplinary approaches span and integrate physics, chemistry and biology, employ a wide range of techniques, and are question driven. We have new projects in each of the above areas as we:
• Pioneer high-throughput quantitative approaches to study enzymes—to address how an entire protein contributes to its function, how allosteric signals are propagated, how different human alleles affect function and/or stability, and ultimately how to design new enzymes (with Polly Fordyce);
• Work to understand the evolution of enzyme function and stability via functional, genome-scale analyses, and experimental evolutionary studies;
• Pioneer the determination of enzyme conformational ensembles—and linking these to function via novel “ensemble¬–function” studies;
• Develop a quantitative and predictive model for RNA tertiary folding thermodynamics and kinetics, building from the “RNA Reconstitution Model”;
• Provide the first quantitative and complete descriptions of the affinity and specificity of RNA binding proteins for all possible RNA sequences and structures (with Will Greenleaf);
• Pioneer Quantitative Cellular Biochemistry (QCB) to bring together the power of biochemistry and genomics to the study molecular interactions and function in cells, with the goal of providing quantitative and predictive models for molecular function and regulation in cells.

Our lab uses cellular, biochemical, and genetic approaches to understand the mechanism by which developmental signaling pathways, such as the WNT and Hedgehog pathways, function and how they are damaged in disease states. We use a broad range of approaches in our work: genome-wide CRISPR screens, proteomics, imaging, and both protein and lipid biochemistry.

A central focus of our laboratory is to uncover new regulatory mechanisms in cell-cell communication system, understand how these mechanisms are damaged in disease states and devise strategies to repair their function. We are actively recruiting post-doctoral fellows to join projects in the following areas:
--Signaling pathways implicated in birth defects, cancer and regeneration.
--Regulation of signaling and development by primary cilia.
--Genetic and biochemical dissection of lipid pathways that regulate signaling, development and cancer.
--The role of biomolecular condensates in cancer and cancer therapeutics.
We strive to provide a supportive, inclusive, organized and collaborative lab environment that maximizes the ability to tackle important biomedical problems. Career development is a priority. Nearly all prior lab members have obtained multiple publications and top-level competitive positions in academics or in the biotech industry.

Department URL:
https://biochemistry.stanford.edu/

Our laboratory studies the dynamics and organization of eukaryotic genomes. Every eukaryotic cell must compact its DNA into the nucleus while maintaining the accessibility of the DNA to the replication, repair, expression and segregation machinery. Eukaryotes accomplish this feat by assembling their genomes into chromatin and folding that chromatin into functional compartments. We are studying four key processes in the eukaryotic nucleus: 1) the genetic and epigenetic basis for centromere formation that enables chromosome segregation, 2) the role of noncoding RNAs in structuring the genome and regulating gene expression, 3) the formation of silent heterochromatin and its role in genome organization and 4) the activation of the embryonic genome at the maternal to zygotic transition. We rely on biochemistry, quantitative microscopy and genomics to probe genome dynamics in vitro and in living systems. Our goal is to uncover the core principles that organize eukaryotic genomes and to understand how genome organization controls organismal function.

Small molecules from the human microbiota. Many of the most widely used human medicines come from soil and marine bacteria, including treatments for cancer, infectious disease, diabetes, and organ transplant. We have recently found that bacteria from a surprisingly underexplored niche -- the human body -- are prolific producers of drug-like small molecules. We are identifying small molecules from gut- and skin-associated bacteria, studying their biosynthetic genes, and characterizing the roles they play in human biology and disease. 
 
Using synthetic ecology to control microbiome metabolism. One of the most concrete contributions the microbiome makes to human biology is to synthesize dozens of metabolites, many of which accumulate in human tissues at concentrations similar to what is achieved by a drug. We are engineering gut and skin bacterial species to produce new molecules, and constructing synthetic communities whose molecular output is completely specified.

Heilshorn's interests include biomaterials in regenerative medicine, engineered proteins with novel assembly properties, microfluidics and photolithography of proteins, and synthesis of materials to influence stem cell differentiation. Current projects include tissue engineering for spinal cord and blood vessel regeneration, designing injectable materials for use in stem cell therapies, and the design of biomaterials for culture of patient-derived biopsies and organoids. Postdoctoral candidates with expertise (or an interest in learning) preclinical animal models of injury and disease are particularly encouraged.

Department URL:
https://mse.stanford.edu

The research interests of the molecular imaging instrumentation lab are to create novel instrumentation and software algorithms for in vivo imaging of molecular signatures of disease in humans and small laboratory animals. These new cameras efficiently image radiation emissions in the form of positrons, annihilation photons, gamma rays, and/or light emitted from molecular contrast agents that were introduced into the body and distributed in the subject tissues. These contrast agents are designed to target molecular pathways of disease biology and enable imaging of these biological signatures in tissues residing deep within the body using measurements made from outside the body.

The goals of the instrumentation projects are to advance the sensitivity and spatial, spectral, and/or temporal resolutions, and to create new camera geometries for special biomedical applications. The computational modeling and algorithm goals are to understand the physical system comprising the subject tissues, radiation transport, and imaging system, and to provide the best available image quality and quantitative accuracy.

The work involves designing and building instrumentation, including arrays of position sensitive sensors, readout electronics, and data acquisition electronics, signal processing research, including creation of computer models, and image reconstruction, image processing, and data/image analysis algorithms, and incorporating these innovations into practical imaging devices.

The ultimate goal is to introduce these new imaging tools into studies of molecular mechanisms and treatments of disease within living subjects.

We work on technology development for genome engineering, discovery-focused synthetic biology, and epigenetic gene therapy. We aim to develop new technologies for studying the mammalian genome and treating complex diseases.

For technology development, we are interested in novel technologies that reprogram the mammalian genome and epigenome. We developed the first nuclease-dead dCas9 from the natural CRISPR-Cas9 nuclease. We developed a series of CRISPR tools that greatly enriched the CRISPR toolbox and expanded genome engineering beyond editing. These tools include CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) for targeted gene activation and repression, LiveFISH for live imaging of DNA and RNA, CRISPR-GO for manipulating the 3D genome organization, and miniature Cas (CasMINI) and hyper-efficient Cas12a (hyperCas12a) for in vivo applications. We harness natural molecules for molecular engineering and evolve novel functions. These tools are broadly used by the community for research and and translational applications.

For discovery-focused synthetic biology, we apply synthetic biology to design and engineer molecules and molecular circuits in mammalian cells. We use synthetic systems to study how cells can be rationally designed as an 'engineering' entity and be harnesses for disease treatment. For example, we engineer T cells to detect new antigens to kill cancer cells or stem cells to integrate environment cues to determine cell fate. By engineering at the scale from molecular to cellular to organismal level, we hope to make synthetic biology a better discovery tool.

For epigenetic gene therapy, we combine epigenome engineering, synthetic biology, and disease models to develop novel therapy to treat cancer, neurodegeneration, and complex genetic diseases. We aim to reveal the importance of noncoding elements including enhancers in the regulation of genome and disease. We harness safe and powerful tools to precisely rewrite the epigenome marks to reverse or cure diseases. We developed PAC-MAN as a treatment to influenza and broad variants of SARS-CoV-2. We aim to greatly expand genome and epigenome engineering towards neurodegenerative diseases and complex diseases.

Flatworms include more than 44,000 parasites, many of which are pathogenic to humans or livestock, with flukes, tapeworms, and hookworms as notorious representative species. They typically transmit through multiple hosts using several drastically different body plans specialized for infecting and reproducing within each host. Although flatworms’ complex life cycles were established over a century ago, little is known about the cells and genes they use to optimize their transmission potential, thereby limiting our ability to develop effective therapeutic and preventive strategies. We aim to develop a comprehensive cellular and molecular understanding of the stereotypical life cycle of a blood fluke, Schistosoma mansoni, and identify novel targets to block it. Schistosomes cause one of the most prevalent but neglected infectious diseases, schistosomiasis. With over 250 million people infected and a further 800 million at risk of infection, schistosomiasis imposes a global socioeconomic burden comparable to that of tuberculosis, HIV/AIDS, and malaria. This project will use novel single-cell technologies to build a schistosome "cell atlas", and map the developmental states of their stem cells as they produce all other cell types in the schistosome body plans.

Biomaterials, medical devices, drug delivery, stem cells and 3D bioprinting for musculoskeletal tissue engineering

Our lab is interested in how stem cell-like populations are created and maintained in developing, environmental responsive tissues.  We primarily use the Arabidopsis stomatal lineage for these studies because this epidermal cell lineage distills features common to all tissue development: stomatal precursor cells are chosen from an initially equivalent field, they undergo asymmetric and self-renewing divisions, they communicate among themselves to establish pattern and they terminally differentiate into stable, physiologically important cell-types.  In the past decade, we have developed the stomatal lineage into a conceptual and technical framework for the study of cell fate, stem-cell self-renewal and cell polarity. Currently, we are especially interested in: (1) using single-cell technologies to capture transcriptomic and chromatin state information about cells as they transit through various identities (stem cell-like, committed, differentiated, and reprogrammed); (2) using new ‘in vivo biochemical’ approaches to identify transcription factor modules in the nuclear and cell polarity complexes at the plasma membrane, and to determine how these complexes guide changes in cell shape, size and fate; (3) computational modeling of pattern formation in the epidermis, and (4) testing how environmental information impacts developmental choices and robustness.

Our lab study neural circuits underlying motivated behaviors and how maladaptive change in these circuits causing neuropsychiatric disorders. We currently focuse on pain and addiction. Both conditions trigger highly motivated behaviors, and the transition to chronic pain and to compulsive drug use involves maladaptive changes of the underlying neuronal circuitry. 

Neuroal circuits mediating opioid addiction:

We established the paraventricular nucleus of the thalamus (PVT) to nucleus accumbens (NAc) pathway as a promising target for treating opioid addiction (Zhu et al., 2016), and revealed the PVT’s role in tracking the dynamics of behavioral relevance and gating associative learning (Zhu et al., 2018).  Using brainwide activity mapping, we identifed a distributed neuronetwork including 23 brain regions that might involve in storing drug-associated memory (Keyes et al, 2020). Ongoing work in the lab is to examining how   

Neuroal circuits underlying descending pain modulation:

We developed a battery of viral, genetic and imaging tools and gained robust access of the mu-opioid receptor expressing spinal cord projecting neurons in the rostromiddel medulla (RVM). We found that these neurons has limited contirbution to nociception in normal mice but is essential for the initiation and maintenance of nerve injury induced chronic pain. We are profiling nerve injury caused gene expression changes in these neurons with the goal to identify key molecular plays that engages these neurons in chronic pain. Based on our finding, we will develop gene therapy reagents and small molecues to treat chronic pain.     

We discover and elucidate new Ca2+-regulated signaling pathways in humans by studying calcineurin, the conserved Ca2+/calmodulin-regulated protein phosphatase. The calcineurin phosphatase dephosphorylates proteins only when Ca2+ signaling is triggered, for example by a hormone, growth factor, neurotransmitter etc. Previous work from the Cyert lab showed how calcineurin allows yeast cells to survive environmental stress (Goldman et al, 2014, Molecular Cell). Currently, we are studying human calcineurin which is ubiquitously expressed and plays critical roles throughout the body, but especially in the nervous, cardiac and immune systems. Calcineurin is best known for activating the adaptive immune response by dephosphorylating the NFAT transcription factors, and is the target of widely prescribed immunosuppressant drugs, FK506 (tacrolimus) and Cyclosporin A. However, these drugs cause many adverse effects due to inhibition of calcineurin in non-immune tissues, where the majority of calcineurin substrates and functions remain to be discovered. We are using a variety of experimental and computational strategies to systematically map human calcineurin signaling pathways in healthy and diseased cells. These rely on identifying Short Linear peptide Motif (SLiMs), i.e. highly variable sequences that reside in regions of intrinsic disorder and mediate specific interactions of substrates and regulators with calcineurin. These approaches have revealed surprising roles for calcineurin  that we are currently studying: in Notch signaling, trafficking though nuclear pores, at centrosomes/cilia, and in regulating phosphoinositide signaling at membranes. A new project is studying calcineurin's role in pancreatitis, where we are identifying calcineurin substrates that mediate the major pathophysiological events that occur during pancreatitis.  We are also interested in understanding how reversible protein lipidation (palmitoylation) is regulated and how palmitoylation impacts calcineurin signaling at membranes by modifying calcineurin itself and some of its regulators.

To learn more about our studies, see our recent papers: Wigington, Roy et al, 2020, Molecular Cell (https://pubmed.ncbi.nlm.nih.gov/32645368/) and Ulengin-Talkish et al, Nature Communications (https://www.nature.com/articles/s41467-021-26326-4).

In the next 50 years, one of the greatest advances we can make for global human health is the realization of a society that is fully sustainable. My research aims to improve agricultural sustainability by using a holistic approach that integrates across genetic, cellular and organismal scales to understand how plants survive stressful environments (Dinneny, 2015a; 2019). Prior research has explored water-stress responses at unparalleled spatial and temporal resolution, and identified the endodermal tissue layer as a critical signaling center for controlling growth and tissue differentiation in roots (Duan et al., 2013; Geng et al., 2013; Dinneny et al., 2008). The discovery of novel adaptive mechanisms used by roots to capture water established potential targets for breeding to improve water use efficiency (Bao et al., 2014; Sebastian et al., 2016). The invention of imaging methods enabled multidimensional studies of plant acclimation and illuminated our understanding of organ system growth from germination to senescence (Rellán-Álvarez et al., 2015; Sebastian et al., 2016). Physiological and molecular insight has been gained in understanding how plants sense water availability through computational modeling of tissue hydraulics (Robbins and Dinneny, 2015, 2018). Additionally, fine-scale biomechanical measurements identified a novel mechanism by which salinity damages cells through its effects on cell-wall integrity (Feng et al., 2018). I have paired my research with a personal passion for improving the education of young plant scientists, engaging lawmakers through science policy, and by being a vocal advocate for the broad deployment of agricultural biotechnology (Fahlgren et al., 2016, Friesner et al., 2021).

Department URL:
https://biology.stanford.edu/people/jose-r-dinneny

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

Although genetics is often taught in terms of simple Mendelian traits, most traits are far more complex. They evolve via a multitude of genetic changes, each having a small effect by itself, which in sum give rise to the spectacular adaptation of every organism to its environment.

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, since this is the primary fuel for natural selection. Our long-term goal is to understand the genetic basis of complex traits well enough to introduce them into new species via genome editing.

The Kopito laboratory seeks a molecular understanding of how cells maintain the fidelity of their proteomes. Unlike DNA, which can be repaired if damaged or incorrectly made, proteins cannot be mended. Instead, damaged or incorrectly synthesized proteins must be rapidly and efficiently destroyed lest they form toxic aggregates. Our laboratory use state-of-the-art cell biological, genetic and systems-level approaches to understand how proteins are correctly synthesized, folded and assembled in the mammalian secretory pathway, how errors in this process are detected and how abnormal proteins are destroyed by the ubiquitin-proteasome system.

Department URL:
https://biology.stanford.edu/

The Kopito laboratory seeks a molecular understanding of how cells maintain the fidelity of their proteomes. Unlike DNA, which can be repaired if damaged or incorrectly made, proteins cannot be mended. Instead, damaged or incorrectly synthesized proteins must be rapidly and efficiently destroyed lest they form toxic aggregates. Our laboratory use state-of-the-art cell biological, genetic and systems-level approaches to understand how proteins are correctly synthesized, folded and assembled in the mammalian secretory pathway, how errors in this process are detected and how abnormal proteins are destroyed by the ubiquitin-proteasome system.

Our research investigates how environmental changes like climate and land use change are affecting infectious diseases in humans and wildlife. We use tools from disease ecology, including mathematical and statistical models, health surveillance data, remotely sensed data, laboratory experiments, and field surveys to better understand the mechanisms by which changes in temperature and habitat affect vectors and disease transmission. 

We study how genetic and environmental factors contribute to biological diversity and adaptation. We are particularly interested in understanding (1) how behavior evolves through changes in brain function and (2) how animal physiology evolves through repurposing existing cellular components.
Our mission is to perform rigorous, ethical, and ecologically relevant science across many areas of organismal biology. We aspire to maintain an environment that fosters creativity, diversity, and inclusion as well as engagement with communities in the areas where we work.
We stand in solidarity with the BlackLivesMatter Movement. Scientists and the institutions we work in are complicit in centuries of racism and we will hold ourselves and our institutions accountable by using lab meetings to reflect on our own privileges and by demanding action from Stanford University. We will continue supporting the careers of our Black colleagues by inviting them to seminars, reading their papers, and promoting their work through collaboration and our social media spaces. We are committed to including classrooms in predominantly Black neighborhoods to our Froggers School Program.

Proteins embedded in the cell envelope of bacteria perform multiple important functions, including signaling, nutrient acquisition, and export of virulence factors. Understanding the structure and functions of these proteins is critical for the development of new anti-bacterial therapies. Currently, the lab focuses on both ABC transporters and lipoproteins of Gram-negative bacteria. The ultimate goal of the research to translate basic lipoprotein research into novel therapuetics.

My goal as a mentor is to contribute to my mentees’ scientific and professional development by leveraging their strengths and providing them with the tools and resources they need to pursue their desired careers. My mentoring philosophy relies on (1) maintaining honest and open communication, (2) providing feedback and guidance, (3) setting clear expectations, and (4) creating a supportive and inclusive learning environment.

We are a chemical biology laboratory focused on the development of technologies to map molecules, cells, and functional circuits. We apply the technologies to understand signaling in the mitochondria and in the mammalian brain.

Our technologies probe molecules and functional networks at both the sub-cellular and multi-cellular level, leveraging our laboratory’s unique strengths in chemical synthesis, protein engineering, directed evolution, proteomics, and microscopy. While we strive to develop technologies that are broadly applicable across biology, we also pursue applications of our methods to neuroscience and mitochondrial biology in our own laboratory and through collaborations.

Our research program is broadly divided into three areas: (1) molecular recorders for scalable, single-cell recording of past cellular events; (2) molecular editors for the precise manipulation of cellular biomolecules, pathways, and organelles; and (3) proximity labeling for unbiased discovery of functional molecules.