PRISM Mentors

We are a machine learning lab with a primary focus on predictive modeling of clinical outcomes using multiomics biological assays. Our research covers a wide range of unconventional yet high-impact topics ranging from space medicine to the integration of mental health, physical health, immune fitness, and nutrition in various clinical settings. We are primarily a computational immunology research group but depending on the problem at hand, our datasets include clinical measurements, readouts from advanced wearable technologies, and various genomics and proteomics assays.
 
Our group has a strong commitment to translating research findings into actionable products. We encourage (and financially support) our postdoctoral fellows to receive extensive training in entrepreneurship and business management from Stanford’s School of Business. This provides an excellent opportunity for a candidate who is not only interested in participating in state-of-the-art academic research, but is also interested in exploring industrial and entrepreneurial career trajectories.

Mission of our group is to “Predict, prevent and alleviate pain”. Broad range of human pain research topics including neuroimaging, transcranial magnetic stimulation, EEG, psychophysics, patient outcomes, learning healthcare systems across many NIH funded projects. Projects include mechanistic characterization of pain to novel treatment developments.

The primary goal of this laboratory is to promote the health and well being of children and adolescents with chronic pain and their families. In line with this goal, research projects focus on biological, neurological, cognitive, affective, and social risk and resiliency factors of the pain experience. Projects include brain imaging, longitudinal clinical cohort, and treatment intervention studies.

We develop algorithms to predict and design the structures and energetics of RNAs and RNA/protein complexes. We test these ideas through community-wide blind trials; by enhancing NMR, crystallographic, and cryoelectron microscopy methods; and by designing new complexes. Upcoming projects involve directly visualizing how natural RNA machines work inside human cells and designing molecules that might enable RNA-based optogenetics, self-replication, and sequence-controlled synthesis of novel polymers.

The FUNR Lab, lead by Flora Rutaganira uses choanoflagellates—the closest living single-celled relatives to animals—to study the origin of animal cell communication. We apply chemical, genetic, and cell biological tools to probe choanoflagellate cell-cell communication. We hope that our research has implications for understanding not only animal cell signaling, but also the origin of multicellularity in animals.

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.

The overall goal of our laboratory is to uncover new regulatory mechanisms in signaling systems, to understand how these mechanisms are damaged in disease states and how to devise new new strategies to repair their function.  Specific areas are highlighted below:

1. The Hedgehog and WNT pathways, two cell-cell communication systems that regulate the formation of most tissues during development. These same pathways play central roles in tissue stem-cell function and organ regeneration in adults. Defects in these systems are associated with degenerative conditions and cancer.

2. Signal transduction at the primary cilium and the mechanism of cilia-associated human diseases. Primary cilia are solitary hair-like projections found on most cells in our bodies that function as critical hubs for signal transduction pathways (such as Hedgehog). Over fifty human genetic diseases, called “ciliopathies,” are caused by defects in cilia. Patients with ciliopathies can show phenotypes in nearly all organ systems, suffering from abnormalities ranging from birth defects to obesity.

3. Regulation of signaling pathways by endogenous lipids. The landscape of endogenous small-molecules and their biological functions remains a terra incognita, one that provides many opportunities to discover new regulatory layers in signaling pathways and other membrane dependent processes.

4. Biomolecular condensates in cancer and cancer therapeutics. The formation of reversible, membrane-less compartments in cells by the segregation of proteins into liquid phases, hydrogels or amyloid-like assemblies is an emerging principle of cellular organization. Emerging evidence shows that some cytotoxic drugs used in oncology can accumulate in and disrupt the biophysical properties of these condensates. A future challenge is to develop strategies to target such membraneless compartments (such as the nucleolus) for effective and safe cancer therapies.

5. Cellular adaptation to extreme tissue environments. Many cells in our bodies can be considered “extremophiles,” charged with maintaining homeostasis in the face of an environment containing markedly non-physiological concentrations of ions, small molecules and toxins. For instance, cells in the kidney medulla face tissue concentrations of ions, urea and other small molecules that are several-fold higher than blood.

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.

Synthetic biology in plants and their associated microbes with the goal of driving innovation in agriculture for a sustainable future.

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.

With a creative, collaborative, biophysical mindset, we aim to understand the ability of parasites to interface with their host-cell to a point at which we can exploit the mechanisms not only for finding cures against the disease the parasites cause but also to make parasite mechanisms a tool that we can use to engineer the host’s cells. By developing approaches that allow a quantitative understanding and manipulation of molecular transport our research transforms parasites from agents of disease to tools for health.

Specifically, we are studying how the malaria parasite takes control over red blood cells. By learning the biophysical principles of transport in between the host and the parasite we can design ways to kill the parasite or exploit it to reengineer red blood cells. The transport we study is broadly encompassing everything from ions to lipids and proteins. We use variations of quantitative microscopy and electrophysiology to gain insight into the unique strategies the parasite evolved to survive.

The Hernandez-Lopez Lab works at the interface of mechanistic, synthetic, and systems biology to understand and program cellular recognition, communication, and organization. We are currently interested in engineering biomedical relevant cellular behaviors for cancer immunotherapy. We are also launching new multidisciplinary projects.

We are looking for outstanding, motivated graduate students and physician-scientists from diverse fields who are interested in joining our interdisciplinary research program. Postdoctoral candidates with expertise (or an interest in learning) preclinical animal models of disease or structural biology (cryo-EM) are particularly encouraged.

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.

Postdoctoral Research Fellow – Cell biology & microfluidics, UCSF & Stanford

A joint postdoc position between the labs of Wallace Marshall (UCSF) and Sindy Tang (Stanford) is immediately available in the area of single-cell wound healing. The broad question we aim to answer is how the single-celled ciliate Stentor can heal drastic wounds. We are looking for a candidate with a background in cell biology or related fields. This position will allow ample opportunities to learn new techniques including microfluidics for single-cell manipulation and mathematical modeling.

Application
For questions or applications (see below), please feel free to reach out to Prof. Wallace Marshall (wallace.ucsf@gmail.com) or Prof. Sindy Tang (sindy@stanford.edu). To apply, please include a CV (with a publication list) and some detail about your background and interest in the project.

Project description:
Biomechanical mechanisms conferring wound resilience in single-celled organisms
Stentor coeruleus is a large, single-celled ciliate that has remarkable wound healing and regenerative capacity (see Slabodnick et al., Current Bio, 2014 https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.10...). It is found in environments that can be subject to high mechanical stresses due to natural flows or predation. The overall goal of this project is to investigate how this organism employs both mechanical and biochemical mechanisms upstream of wounding for wound prevention, as well as downstream of wounding for robust healing from wounds (https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-021-00970-0).

We have sequenced the Stentor genome, and developed tools for molecular manipulation of Stentor gene expression to pave the way to a molecular understanding of Stentor wound response.   This project involves conceptualization of a novel chemical screen to test the role of the cytoskeleton in conferring wound resistance to the cell, and the role of large-scale mechanical force generation in complementing biochemical healing modes to close wounds of increasing severity.

Some questions we ask are: how does Stentor cell mechanics give rise to wound resistance? How do cells respond to shear or other types of stresses? What molecular pathways are important in Stentor wound healing, and are they the same as in other eukaryotes?
The project combines cell biology, microfluidics for precise wounding (see Blauch et al., PNAS 2017 https://www.pnas.org/doi/abs/10.1073/pnas.1705059114), and mechanobiology modeling.

Required Qualifications:
Desired skills for this project include:
• Cell biology
• Chemical screen
• RNAi and genetic transformation
• Past experience with Stentor, other ciliates, or manipulation (e.g., microinjection) of large cells or embryos such as Drosophila
• Mathematical modelling of cellular processes
Candidates proficient in certain skills outlined above will have opportunities to receive training in complementary skill sets.

Required Application Materials:
Your CV with a publication list, and some detail about your background and interest in the project.

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.     

By studying calcineurin, the conserved Ca2+/calmodulin-regulated protein phosphatase, we aim to discover and elucidate new Ca2+-regulated signaling pathways in humans. 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 discovered 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. We have uncovered surprising roles for calcineurin in Notch signaling, regulation of transport though nuclear pores, and at centrosomes. See our recent paper (Wigington, Roy et al, 2020, Molecular Cell) to learn more about our studies.

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.