Immunologists & Clinicians Probe Human, Animal & Microbial Systems to Decipher Diseases, Find Treatments
Nadine Taylor-Barnes | April 20, 2020
The research presented at the 30th anniversary illustrated Mark Davis’ point about the immune system as a key arbiter of health or disease, underlying both states. The presentations spanned basic science research, deciphering disease signatures using the latest technologies, methods of studying the human immune system directly, taking a systems immunology view, and providing the investment ecosystem to support and realize the research.
Unraveling Disease Signatures with Technology
In crafting disease signatures, a “data model” for diseases, immunologists define many different attributes in order to identify a disease, check its status, and predict its recurrence, ideally, before it resurfaces. In doing this, scientists also have the opportunity to intervene while cells are developing in order to change the progression of their development and ultimately the disease. Also, they are examining the microenvironments around cells and how different cells influence each other.
“Pathology from the molecular scale on up”
Faculty member Garry Nolan, PhD, Genetics 1989, Baxter Labs/Microbiology & Immunology, uses bioinformatics and high-dimensional imaging machines to visualize single cells and measure many characteristics of each cell. He is also creating detailed cell phenotypes and vivid images of cell neighborhoods from CyTOF, Codex and MIBI machines, allowing the visualization of cells and tissues with multiple markers and the development of network models of signaling pathways.
“We can use algorithms to segment cells and show how they interact with each other. No cell acts independently,” he said, “and differentiation is a continuous trajectory -- not a chain of discrete stages, as we once thought. It’s in these transition points that the proteins are undergoing many changes, and we can use algorithms, essentially reducing the cell development stages to mathematical equations, to determine recurrence.” He spoke about how artificial intelligence, being used for cell segmentation, is driving this area forward.
“Guiding T-lymphocyte differentiation in cancer immunotherapy applications”
Zina Good, PhD, 2018, a postdoctoral fellow in the Crystal Mackall Lab, Pediatrics, wants to identify systems-wide immune system processes that are required to wage a coordinated attack against cancer. Continuing the research begun under her mentors Garry Nolan, PhD, and Sean Bendall, PhD, Good demonstrated the value of understanding T cell differentiation processes in order to then “guide T cells towards desired outcomes, such as steering T cells towards differentiation states that are more potent in combatting cancer.” She hopes that understanding these processes will enable scientists to intervene at critical junctures to boost the effectiveness of these cells.
Good described a method for deep single-cell phenotyping, measuring 30-plus features for every cell, across division states during critical differentiation periods in the context of cell expansion for immunotherapy. “We have an opportunity to intervene at the relevant time points, and perhaps guide T cell differentiation towards a desirable phenotype,” Good said.
“Methods for systems immunology analysis of inflammatory disease”
Purvesh Khatri, PhD, Postdoc 2008, Faculty, Medicine & Biomedical Informatics/ITI, who is leading the Computational and Systems Immunology track of the PhD Program, talked about the importance of analyzing heterogeneity, or differences among individuals, to help cure diseases. “Traditionally, biologists looked for uniformity across a group,” he said. “In the world of precision medicine, this big data approach can help individuals by predicting their unique immune response to vaccinations, infections, autoimmune diseases, and organ transplants.”
After gathering volumes of disease and treatment data from NIH and public sources, on healthy and ill patients, Khatri is “interrogating” the data. He is looking at gene signatures, different immune cell types and how they change. “I want to bring molecular science together with clinical records.” He hopes to create “data models” of diseases and to identify biomarkers to help predict clinical outcomes in, for example, sepsis, fibrosis, and bacterial and viral infections. This approach can be used for drug repurposing, finding new uses for medications from the database of approved pharmaceuticals. Also, he is creating profiles of an individual’s immune system status to predict his or her unique response to vaccinations or illness.
“Understanding immune responses to cancer from quantitative single-cell models”
Alumnus Matt Spitzer, PhD, 2016, Faculty, Otolaryngology, Microbiology & Immunology, UCSF, described tumor microenvironments and how the different immune cells – T cells, B cells, macrophages, dendritic cells, monocytes, and neutrophils -- coordinate their response to a tumor.
While at Stanford, he developed a computational platform using an algorithm named SCAFFOLD to visualize immune cell clusters, their stages of development, and their relationships to each other across an entire organism, essentially creating a “picture” of a person’s total immune state.
“The context is critical,” he said, “and current studies have not been coordinated. Successful immunotherapy involves widespread activation of the immune system in places far from the tumor – in lymph nodes, bone marrow and blood. A systemic response, not just a local response, is required for tumor eradication, and effective immunotherapies need systemic training.”
He then discussed a new project in his lab that is looking at an integrative model of immune states and the immune system’s ability to respond to changes over time as it is influenced by diet, gender and the environment. There are over 40 clinical trials at UCSF now in this area.
“Perturbation of the metabolic phenotypes of vaccination by the microbiome in humans”
Faculty member Bali Pulendran, PhD, Pathology/ ITI, has taken a big data “systems immunology” approach to determine “molecular signatures” induced by vaccines. His goal is to extract biological insight from these analyses to advance the development of new vaccines against global pandemics.
“Vaccines are a great way to probe the human immune system because they represent a diverse array of microbial stimuli, and allow a very synchronized perturbation, or alteration, of the human immune system. Coupling this data with other precise measurements of individuals’ health, referred to as ‘Omics,’ provides a unique conceptual framework to assess the impact of many factors: individuals’ genetics, their microbiomes, and environmental factors, in programming the molecular networks underpinning their immunity,” he said.
He presented data from a human experiment, in which healthy volunteers were administered a cocktail of antibiotics, and vaccinated with the influenza vaccines, to assess the impact of the microbiome on immunity to vaccination. The results reveal a remarkable alteration of their metabolic phenotypes, and an effect of the microbiome on the quality of the innate and adaptive response to vaccination.
“Decoding immunity: An ode to libraries gone right and libraries gone wrong”
Alumnus Michael Birnbaum, PhD, 2014, Faculty, Biological Engineering, MIT, said he has been “between biology and chemistry, basic and applied, but the molecule that brought me to Stanford, was the T cell receptor.” Now, he has made it his goal to create the most comprehensive library of human antigens so that researchers can use it to direct therapeutics.
“If you know which T cell binds to which peptide, one can more precisely direct the therapeutics,“ he said. “One goal is to create personal neoantigen vaccines to improve a person’s response to immunotherapy.” At present, no comparable database exists.
Interrogating the Human Immune System to Discover Therapeutic Targets
In studying the human immune system directly, researchers can pinpoint the actions of pathogens and how they escape detection, how cells and molecules regulate each other, and how to engineer immune cells for treatment.
“Deconstructing the oncogenic pathways of Epstein-Barr Virus in B cells”
Olivia Martinez, PhD, Faculty, Surgery, and Director of PhD Program in Immunology, and Director of Stanford Immunology, investigates the Epstein-Barr Virus (EBV) in humans and its ability to not only remain latent within a person’s body for decades but also escape detection by the immune system. She is also looking at how the virus can induce B cell lymphomas.
Using human samples taken over a period of time, Martinez examines how the virus changes a person’s B cells during that period and how the T cells respond to these EBV-infected B cells. She is studying a signaling molecule that the virus produces to regulate and change the host’s immune system.
Martinez believes that this very mechanism could be targeted in lymphoma cancer cells, thereby inhibiting tumor growth. Additionally, she believes this molecule could be a biomarker to check for the development of lymphoma and is conducting a five-year clinical trial study in children. Other ongoing studies are defining, on a single cell level, the characteristics of the immune response that distinguish the ability to successfully control the virus following infection.
“Engineering T cells for cancer therapy”
Crystal Mackall, MD, Faculty, Pediatrics/Hematology/Oncology; Director, Parker Institute for Cancer Immunotherapy and Stanford Center for Cancer Cell Therapy, is engineering T cells for cancer therapy in a new way. She is designing receptors on the surface of T cells that can simultaneously target multiple tumor antigens, rather than just one. The antigens are proteins that identify the tumor cells. “Cancer is heterogeneous, therefore, in order to effectively target the entire tumor, we need to engineer protein designs that are multi-specific.” Her group was the first to launch the bivalent chimeric antigen receptor (CAR) capable of recognizing CD19 or CD22 on B cell malignancies, thus precisely attacking tumor cells from multiple angles.
Mackall is also developing new approaches to enhance the potency of engineered T cells by studying the biological changes that occur within T cells when they differentiate in response to antigen. In the presence of prolonged antigen stimulation, Mackall’s group has demonstrated that CAR T cells acquire hallmark features of T cell exhaustion associated with altered gene transcriptional profiles. By engineering overexpression of transcription factors diminished in the presence of T cell exhaustion, CAR T cells can get endowed with greater potency against cancer.
“The genesis of Rheumatoid Arthritis”
While examining the mechanisms that control the progression of autoimmune diseases, such as Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS), Faculty member Bill Robinson, MD, PhD, 1996, Medicine/Immunology & Rheumatology, discovered two different immune system pathways that operate synergistically to induce RA. Additionally, he found subtypes of RA and identified their distinct molecular signatures, which could provide opportunities for targeting drugs to subpopulations of patients. He is also investigating the impact of environmental factors on the development of RA in humans.
“Anti-interleukin-1 receptor antagonist autoantibodies promote inflammation and fibrosis in patients with a rare and fatal autoimmune disease”
Alumnus Justin Jarrell, PhD, 2018, while in Robinson’s lab, Medicine/Immunology & Rheumatology, not only discovered a new target for patients suffering from a rare autoimmune disease called IgG4-Related Disease, but also how a FDA-approved drug could be re-purposed to counter it. Jarrell is now Director of Research, Indee Labs.
“The imp in the bottle: Can a common household chemical be the missing link to unexplained chronic pain?”
Alumna Devavani Chatterjea, PhD, 2001, Faculty, Biology, Macalester College, runs a lab researching T cell development, stromal cell signaling, and the role of mast cells in inflammatory and chronic pain. She heard about a rare gynecological condition, Vulvodynia, that causes debilitating pain, and for which there was no underlying cause.
Chatterjea described how she, “Put two and two together and figured out that this condition could be an immune system disorder.” As such, she was the first to discover mast cells controlling the immune response and pain in Vulvodynia and is now investigating its links to common preservatives found in cosmetics, personal care products, and household cleaners.
“Shuffling CARDs in immunodeficiency”
Alumnus Andy Snow, PhD, 2005, Faculty, Pharmacology, Uniformed Services University of the Health Sciences, also talked about the “importance of seeing immunodeficient patients and learning about the human immune system directly from them. It’s non-traditional to start with humans,” he said. “In fact, it is the reverse process of how we usually learn by starting with the animal model.”
Snow is investigating how inherited mutations in the CARD 11 signaling protein can give rise to multiple immune disorders in humans, featuring frequent viral/bacterial infections, eczema or lymphocytosis. By examining how these basic mechanisms of immune cell signaling are perturbed, Snow hopes it may lead scientists to find pathways for intervention.
“Studying innate immunity in the human airway”
Alumna Ellen Foxman, MD, 2001, PhD, 1999, Faculty, Laboratory Medicine, Yale University School of Medicine, discussed the importance of “using humans to study basic human immunology, to figure out what our body is doing right to fight infection.”
She pointed to her research on how rhinovirus infection in human airways can vary greatly. Considering that the virus is the number one cause of colds and asthma attacks, the virus is also frequently cleared from the airway without causing symptoms. She demonstrated how an individual’s recent exposures can alter local antiviral defenses and determine whether or not rhinovirus can replicate. “One’s ability to fight the virus can depend upon a number of factors -- age, smoking, asthma – and even ambient air temperature.”
“Understanding the role of regulatory T cells in immunological tolerance: From bedside to bench and back”
Maria Grazia Roncarolo, MD, Faculty, Pediatrics and Medicine/Stem Cell Transplantation, discovered a new class of T cells, named regulatory type 1 T cells, that help prevent autoimmune conditions. She is studying the human immune system to understand how deficiencies in different subsets of regulatory T cells can lead to allergy, chronic inflammatory and autoimmune diseases.
“Patients with genetic disorders in regulatory T cells are unique models to better understand the role of regulatory T cells,” she said. “These studies could lead to regulatory T cell therapy in the near future – perhaps eliminating the need for suppressing the entire immune system with very toxic, immunosuppressive drugs.”
Roncarolo listed about twenty diseases that might be curable using this method, including: transplant rejection and graft-versus-host disease, and autoimmune and inflammatory diseases, such as, Type 1 Diabetes, MS, and IBD.
“Teaching natural killers to cure”
Catherine Blish, MD, PhD, Faculty, Medicine/Infectious Diseases, focuses on the biology and sheer diversity of natural killer (NK) cells and how to harness their innate abilities to target tumors and infections. NK cells recognize and attach to infected cells or cancer cells, then release enzymes and other substances that damage the outer membranes of these cells.
Blish is looking at the NK cell’s role in infectious diseases and believes that “starting with a systems immunology approach can lead to new insights that are directly relevant to human health.” She is investigating designing NK cells that contain distinct proteins which would enable the NK cells to kill tumors.
Researchers described how they are further investigating even broader roles of immune cells.
“High-dimensional characterization of human dendritic cell subsets”
Rebecca Leylek, graduate student, Juliana Idoyaga Lab, Microbiology & Immunology, is characterizing and defining the human dendritic cell (DC) subsets – using CyTOF. When considering the cells’ role of presenting both foreign antigens and self-antigens to the immune system, these cells could be the basis for cell-based vaccines in the future. “I am looking both at the differences in DC subset distribution among tissues within an individual, and at differences among individuals,” she said.
“The fast track to T cell development”
Alumna Lauren Richie Ehrlich, PhD, Faculty, Molecular Biosciences, The University of Texas, Austin, described T cell development and how these cells gain the ability to distinguish between self and non-self. T cells, as master regulators of the adaptive immune system, are essential for coordinating the appropriate immune response to different pathogens, and are responsible for immunologic memory, which protects us from recurrent infections.
Ehrlich detailed the system of checks and balances that take place within individuals, as T cells develop, because “deviations in normal cell interactions are thought to contribute to diseases such as T cell lymphoma and autoimmunity.” Ehrlich is applying advanced imaging approaches to elucidate the molecular and cellular mechanisms by which developing T cells encounter the diverse array of self-antigens present throughout the body to ensure broad self-tolerance to avert autoimmunity.
“Holy Cow! Diversity of ultra-long CDR3 bovine antibodies”
Alumnus Vaughn Smider, MD, PhD, Faculty, Molecular Medicine, The Scripps Research Institute, looked at how other animals – specifically cows – have evolved antibodies with elongated ‘knob structures” that enable these antibodies to attach to complex viruses. HIV, an example of a complex virus, has a highly developed mechanism to escape detection by a person’s immune system. Smider believes that scientists can copy the structural properties of cow antibodies and engineer new classes of antibodies for therapeutic use.
“Velcro-like pericellular matrix interactions stabilize immune synapse, critical for antigen presentation”
Payton Marshall, graduate student, MSTP, Paul Bollyky Lab, Medicine/Infectious Diseases, spoke about the participation of hyaluronan at the immune synapse, and how it is critical for the presentation of antigens.
“Pf bacteriophage as novel pathogenic factors in Pseudomonas aeruginosa infections”
Alumna Jolien Sweere, Paul Bollyky Lab, Medicine/Infectious Diseases, is examining bacteriophages, viruses that are very effective at infecting bacteria, in order to find how they affect both the bacteria and the mammalian host’s immune system. “These findings,” she said, “could offer novel insights for treatment of infections in humans.”
“Conserved inflammatory signaling modulates resistance & repair during microbial dysbiosis in regenerative flatworm Schmidtea mediterrannea”
Alumnus Chris Arnold, PhD, postdoctoral fellow, Sanchez Lab, Stowers Institute for Medical Research, is investigating how tissue regeneration can be helped or hurt by inflammation. He is using the planaria organism but hopes that this work can lead to ways to encourage tissue repair after surgery or in wound healing.
Investment Ecosystem for Biomedicine
Once promising discoveries are made in the lab, so begins an arduous, multi-year process requiring additional research and multiple trials to develop treatments or medications that can ultimately help patients. The investment infrastructure that supports this work comes into play.
“Walk on the wild side: Alternative careers in drug discovery & development”
Alumnus James Healy, MD, 1998, PhD, 1998, President and General Partner, Sofinnova Investments, a life science investment firm, discussed the importance of biotechnology drug discovery and development outside the university setting. Dr. Healy earned his MD and PhD following “a serpentine route to Stanford and my vocation after growing up in Montana and living in Hawaii, Utah and Denmark.” He smiled, “Venture capital was not my planned career.” He went on to say “We need scientists with razor-sharp skills in the biotech industry to bring treatments to the market for patients. My firm has funded over 60 companies and nearly 100 clinical programs in the past dozen years.”
From basic science research, to unraveling disease signatures, to interrogating the human immune system, to developing therapeutic treatments for patients, the community of Stanford immunologists has much to celebrate – and much to look forward to.