Keystone Symposium Research Articles

Geographic Equity and Environmental Sustainability of Conference Models: Results of a Comparative Analysis.

We conducted a comparative analysis of in-person, virtual, and hybrid conferences on tuberculosis hosted by Keystone Symposia and examined the number of participants, their country of residence, carbon dioxide equivalents (CO2e) produced, and participant impressions regarding scientific quality. Data were available from three in-person meetings, one virtual meeting, and one hybrid. The virtual conference hosted 2.5-fold more participants compared with the in-person conferences (842 versus an average of 328) from more than double the number of countries (68 versus an average of 33). The virtual conference attracted 4.5-fold more participants from countries with a high burden of tuberculosis, compared with the average in-person conference (209 versus an average of 46). For in-person meetings, an average of 79% of participants were based in high-income countries. For the virtual meeting, 53% of participants were from high-income countries, and 47% from low- and middle-income countries. For the hybrid conference, there were 465 participants from 43 countries, of which 289 attended in person from a total of 20 countries, and 176 participated virtually from 34 countries. Of those who took part in person, 91% were from high-income countries. The average CO2e emissions from an in-person conference was 696 tons of CO2e, with 96.0% from air travel. The virtual meeting produced 0.48 ton of CO2e from electricity usage, a 1,450-fold decrease compared with in-person events. Virtual conferences scored a content quality rating of 87.3% to 90.8% compared with a range of 86.4% to 92.2% for in-person conferences.

New Approaches in Heart Research: Prevention Instead of Cardiomyoplasty?

Cardiovascular diseases are the leading cause of death in industrialized nations. Due to the high number of patients and expensive treatments, according to the Federal Statistical Office (2017) in Germany, cardiovascular diseases account for around 15% of total health costs. Advanced coronary artery disease is mainly the result of chronic disorders such as high blood pressure, diabetes, and dyslipidemia. In the modern obesogenic environment, many people are at greater risk of being overweight or obese. The hemodynamic load on the heart is influenced by extreme obesity, which often leads to myocardial infarction (MI), cardiac arrhythmias, and heart failure. In addition, obesity leads to a chronic inflammatory state and negatively affects the wound-healing process. It has been known for many years that lifestyle interventions such as exercise, healthy nutrition, and smoking cessation drastically reduce cardiovascular risk and have a preventive effect against disorders in the healing process. However, little is known about the underlying mechanisms, and there is significantly less high-quality evidence compared to pharmacological intervention studies. Due to the immense potential of prevention in heart research, the cardiologic societies are calling for research work to be intensified, from basic understanding to clinical application. The topicality and high relevance of this research area are also evident from the fact that in March 2018, a one-week conference on this topic with contributions from top international scientists took place as part of the renowned "Keystone Symposia" ("New Insights into the Biology of Exercise"). Consistent with the link between obesity, exercise, and cardiovascular disease, this review attempts to draw lessons from stem-cell transplantation and preventive exercise. The application of state-of-the-art techniques for transcriptome analysis has opened new avenues for tailoring targeted interventions to very individual risk factors.

Progress in vaccine development for infectious diseases-a Keystone Symposia report.

The COVID-19 pandemic has taught us many things, among the most important of which is that vaccines are one of the cornerstones of public health that help make modern longevity possible. While several different vaccines have been successful at stemming the morbidity and mortality associated with various infectious diseases, many pathogens/diseases remain recalcitrant to the development of effective vaccination. Recent advances in vaccine technology, immunology, structural biology, and other fields may yet yield insight that will address these diseases; they may also help improve societies' preparedness for future pandemics. On June 1-4, 2022, experts in vaccinology from academia, industry, and government convened for the Keystone symposium "Progress in Vaccine Development for Infectious Diseases" to discuss state-of-the-art technologies, recent advancements in understanding vaccine-mediated immunity, and new aspects of antigen design to aid vaccine effectiveness.

Immunometabolism at the crossroads of obesity and cancer-a Keystone Symposia report.

Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed. On September 5-8, 2022, experts in the field of immunometabolism met for the Keystone symposium "Immunometabolism at the Crossroads of Obesity and Cancer" to present recent research across the field of immunometabolism, with the setting of obesity and cancer as an ideal example of the complex interplay between metabolism, immunity, and cancer. Speakers highlighted new insights on the metabolic links between tumor cells and immune cells, with a focus on leveraging unique metabolic vulnerabilities of different cell types in the tumor microenvironment as therapeutic targets and demonstrated the effects of diet, the microbiome, and obesity on immune system function and cancer pathogenesis and therapy. Finally, speakers presented new technologies to interrogate the immune system and uncover novel metabolic pathways important for immunity.

Exosomes, microvesicles, and other extracellular vesicles-a Keystone Symposia report.

Extracellular vesicles (EVs) are small, lipid-bilayer-bound particles released by cells that can contain important bioactive molecules, including lipids, RNAs, and proteins. Once released in the extracellular environment, EVs can act as messengers locally as well as to distant tissues to coordinate tissue homeostasis and systemic responses. There is a growing interest in not only understanding the physiology of EVs as signaling particles but also leveraging them as minimally invasive diagnostic and prognostic biomarkers (e.g., they can be found in biofluids) and drug-delivery vehicles. On October 30-November 2, 2022, researchers in the EV field convened for the Keystone symposium "Exosomes, Microvesicles, and Other Extracellular Vesicles" to discuss developing standardized language and methodology, new data on the basic biology of EVs and potential clinical utility, as well as novel technologies to isolate and characterize EVs.

Respiratory viruses: New frontiers-a Keystone Symposia report.

Respiratory viruses are a common cause of morbidity and mortality around the world. Viruses like influenza, RSV, and most recently SARS-CoV-2 can rapidly spread through a population, causing acute infection and, in vulnerable populations, severe or chronic disease. Developing effective treatment and prevention strategies often becomes a race against ever-evolving viruses that develop resistance, leaving therapy efficacy either short-lived or relevant for specific viral strains. On June 29 to July 2, 2022, researchers met for the Keystone symposium "Respiratory Viruses: New Frontiers." Researchers presented new insights into viral biology and virus-host interactions to understand the mechanisms of disease and identify novel treatment and prevention approaches that are effective, durable, and broad.

Viral immunity: Basic mechanisms and therapeutic applications-a Keystone Symposia report.

Viruses infect millions of people each year. Both endemic viruses circulating throughout the population as well as novel epidemic and pandemic viruses pose ongoing threats to global public health. Developing more effective tools to address viruses requires not only in-depth knowledge of the virus itself but also of our immune system's response to infection. On June 29 to July 2, 2022, researchers met for the Keystone symposium "Viral Immunity: Basic Mechanisms and Therapeutic Applications." This report presents concise summaries from several of the symposium presenters.

Positive-strand RNA viruses-a Keystone Symposia report.

Positive-strand RNA viruses have been the cause of several recent outbreaks and epidemics, including the Zika virus epidemic in 2015, the SARS outbreak in 2003, and the ongoing SARS-CoV-2 pandemic. On June 18-22, 2022, researchers focusing on positive-strand RNA viruses met for the Keystone Symposium "Positive-Strand RNA Viruses" to share the latest research in molecular and cell biology, virology, immunology, vaccinology, and antiviral drug development. This report presents concise summaries of the scientific discussions at the symposium.

Collaboration and knowledge integration for successful brain therapeutics – lessons learned from the pandemic

Brain diseases are a major cause of death and disability worldwide and contribute significantly to years of potential life lost. Although there have been considerable advances in biological mechanisms associated with brain disorders as well as drug discovery paradigms in recent years, these have not been sufficiently translated into effective treatments. This Special Article expands on Keystone Symposia's pre- and post-pandemic panel discussions on translational neuroscience research. In the article, we discuss how lessons learned from the COVID-19 pandemic can catalyze critical progress in translational research, with efficient collaboration bridging the gap between basic discovery and clinical application. To achieve this, we must place patients at the center of the research paradigm. Furthermore, we need commitment from all collaborators to jointly mitigate the risk associated with the research process. This will require support from investors, the public sector and pharmaceutical companies to translate disease mechanisms into world-class drugs. We also discuss the role of scientific publishing in supporting these models of open innovation. Open science journals can now function as hubs to accelerate progress from discovery to treatments, in neuroscience in particular, making this process less tortuous by bringing scientists together and enabling them to exchange data, tools and knowledge effectively. As stakeholders from a broad range of scientific professions, we feel an urgency to advance brain disease therapies and encourage readers to work together in tackling this challenge.

Antibodies as drugs-a Keystone Symposia report.

Therapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to identify antibodies with therapeutic potential as well as methods to improve upon endogenous antibodies and to design antibodies de novo. On April 27-30, 2022, experts in antibody research across academia and industry met for the Keystone symposium "Antibodies as Drugs" to present the state-of-the-art in antibody therapeutics, repertoires and deep learning, bispecific antibodies, and engineering.

Lessons from the pandemic: Responding to emerging zoonotic viral diseases-a Keystone Symposia report.

The COVID‐19 pandemic caught the world largely unprepared, including scientific and policy communities. On April 10–13, 2022, researchers across academia, industry, government, and nonprofit organizations met at the Keystone symposium “Lessons from the Pandemic: Responding to Emerging Zoonotic Viral Diseases” to discuss the successes and challenges of the COVID‐19 pandemic and what lessons can be applied moving forward. Speakers focused on experiences not only from the COVID‐19 pandemic but also from outbreaks of other pathogens, including the Ebola virus, Lassa virus, and Nipah virus. A general consensus was that investments made during the COVID‐19 pandemic in infrastructure, collaborations, laboratory and manufacturing capacity, diagnostics, clinical trial networks, and regulatory enhancements—notably, in low‐to‐middle income countries—must be maintained and strengthened to enable quick, concerted responses to future threats, especially to zoonotic pathogens.

1 Oral - A radiohapten capture system for CAR T cells that tracks them in vivo and improves efficacy

Background: CAR T cell therapy has become an important therapeutic tool for the treatment of B-cell neoplasms. However, the development of CAR T cell therapy outside of hematologic malignancies has stalled. As such, there is an unmet need to understand why CAR T cell therapy fails, which would be aided through the creation of tools to track them in vivo. Additionally, endowing CAR T cells with potent orthogonal anti-tumor activity has emerged as a strategy to improve upon CAR T cell efficacy. To accomplish both goals, we engineered a class of theranostic “THOR” CAR T cells that express a membrane-bound scFv, huC825, that binds DOTA-radiohaptens with pM affinity; these hapten chelands can be conjugated with radionuclides with therapeutic potential or diagnostic imaging capabilities. Methods: We engineered 19BBZ anti-CD19 CAR T cells to express huC825 (THOR CAR T cells) and confirmed transduction of these cells with flow cytometry. To assess the cytolytic ability and effector function of THOR CAR T cells, we used the Matador co-culture assay and measured the cytokine secretion of these co-cultures. We tested the potential to track THOR CAR T cells in vivo using PET/CT following intravenous DOTA-based radiohapten tracer administration in immunodeficient (NSG) mice bearing subcutaneous CD19+ Raji tumors. We also tested the ability of THOR CAR T cells to synergize with therapeutic radionuclide therapy. We evaluated the anti-tumor efficacy using whole animal bioluminescence imaging, tumor size measurements, and median animal survival. Results: We successfully transduced THOR CAR T cells, which demonstrated similar in vitro anti-tumor effects and cytokine secretion as parent 19BBZ CAR T cells. In vivo tracking experiments with 86Y-DOTA-Bn radiotracer showed that THOR CAR T cells can be observed at day 7 post T cell administration, peak at day 14, and persist until at least day 28. 86Y-DOTA-Bn uptake was specific to THOR CAR T cells, as minimal uptake was observed in mice transplanted with 19BBZ CAR T cells. Importantly, we noted rapid renal clearance of unbound tracer resulting in high contrast images. In efficacy assays in vivo, we demonstrated the synergy between 225Ac-Proteus-DOTA and THOR CAR T cells, as shown by a significant decrease in tumor burden and increase in median survival (THOR CAR treated = 26 days, treated with THOR CAR plus 225Ac-Proteus-DOTA = 32 days, p = .04, n = 6 per group). In contrast, mice receiving 19BBZ CAR T cells with or without 225Ac-Proteus-DOTA showed no improvements in antitumor efficacy. Conclusions: We show the pharmacokinetics of THOR CAR T cells can be probed in vivo following systemic administration of radiotracer using serial PET/CT imaging. Furthermore, we demonstrate a CAR T cell can be potentiated by systemically administered cytotoxic radionuclide that are then delivered selectively to tumors by the THOR cells. Conflict of interest: Ownership: MSK has filed for patent protection on behalf of M.M.D, S.M.C., D.R.V., B.H.S., N.K.C., D.A.S., S.M.L. and S.K. for inventions related to this work. Advisory Board: N.K.C. is an advisor to, or owns equity in Abpro, Alexs Lemonade Stand Foundation, Biotec Pharmacon, Eureka Therapeutics, Keystone Symposia, Partner Therapeutics, St. Jude-VIVA Forum, and Y-mAbs Therapeutics that may work in areas related to this study. Other Substantive Relationships: S.M.C. has licensed IP to Y-mAbs.

Engineering multicellular living systems-a Keystone Symposia report.

The ability to engineer complex multicellular systems has enormous potential to inform our understanding of biological processes and disease and alter the drug development process. Engineering living systems to emulate natural processes or to incorporate new functions relies on a detailed understanding of the biochemical, mechanical, and other cues between cells and between cells and their environment that result in the coordinated action of multicellular systems. On April 3-6, 2022, experts in the field met at the Keystone symposium "Engineering Multicellular Living Systems" to discuss recent advances in understanding how cells cooperate within a multicellular system, as well as recent efforts to engineer systems like organ-on-a-chip models, biological robots, and organoids. Given the similarities and common themes, this meeting was held in conjunction with the symposium "Organoids as Tools for Fundamental Discovery and Translation".

Organoids as tools for fundamental discovery and translation-a Keystone Symposia report.

Complex three-dimensional in vitro organ-like models, or organoids, offer a unique biological tool with distinct advantages over two-dimensional cell culture systems, which can be too simplistic, and animal models, which can be too complex and may fail to recapitulate human physiology and pathology. Significant progress has been made in driving stem cells to differentiate into different organoid types, though several challenges remain. For example, many organoid models suffer from high heterogeneity, and it can be difficult to fully incorporate the complexity of in vivo tissue and organ development to faithfully reproduce human biology. Successfully addressing such limitations would increase the viability of organoids as models for drug development and preclinical testing. On April 3-6, 2022, experts in organoid development and biology convened at the Keystone Symposium "Organoids as Tools for Fundamental Discovery and Translation" to discuss recent advances and insights from this relatively new model system into human development and disease.

Keystone Malaria Symposium 2022: a vibrant discussion of progress made and challenges ahead from drug discovery to treatment

Keystone Malaria Symposium 2022: a vibrant discussion of progress made and challenges ahead from drug discovery to treatment

Outtakes from My Journey through the World of LIPID MAPS.

My laboratory’s research on lipids has focused on phospholipases and lipidomics and in many ways has evolved in parallel to the evolution of the lipid field over the past half century. I have reviewed our research elsewhere. Herein, I describe the “side stories” or “outtakes” that parallel the main story that focuses on our laboratory’s research. I will emphasize the importance of community activities and describe how I came to initiate and lead the international effort on the Lipid Metabolites and Pathways Strategy (LIPID MAPS). Several of these side activities had a significant effect on discoveries in my laboratory research and its evolution as well as contributing significantly to the development of the LIPID MAPS initiative. These included experience and influences from serving as Editor-in-Chief of the Journal of Lipid Research and Chair and President of the Keystone Symposia on Cell and Molecular Biology as well as other experiences in organizing lipid conferences, teaching on lipid structure and mechanism, and earlier formative administrative and leadership experiences. The relevant influences are summarized herein.

Erica Ollmann Saphire: How the Study of HIV and Other Viruses Informed the Rapid Development of Vaccines and Therapeutic Antibodies Against COVID-19.

Neil Greenspan, professor of pathology at Case Western Reserve University and senior editor at Pathogens and Immunity talks with Erica Ollmann Saphire, President and Chief Executive Officer of the La Jolla Institute for Immunology, about her work on hemorrhagic fever viruses and SARS-CoV-2. She'll be speaking about these topics at the Keystone Symposium, Lessons from the Pandemic: Responding to Emerging Zoonotic Viral Diseases. Dr. Sapphire is an eminent structural biologist devoted to understanding viral pathogens and pathogenesis.

Metabolic decisions in development and disease.

The intimate relationships between cell fate and metabolism have long been recognized, but a mechanistic understanding of how metabolic pathways are dynamically regulated during development and disease, how they interact with signalling pathways, and how they affect differential gene expression is only emerging now. We summarize the key findings and the major themes that emerged from the virtual Keystone Symposium 'Metabolic Decisions in Development and Disease' held in March 2021.

AAA+ proteins: converging mechanisms, diverging functions.

The second Keystone Symposium on AAA+ proteins, “AAA+ Proteins: From Atomic Structures to Organisms”, was held in Tahoe City, USA in January 2020. The program highlighted recent advances from structural, biochemical and cellular approaches that have extended our understanding of these important ATP-driven molecular machines.

Origins of allergic disease: Maternal and early childhood factors

The incidence of allergic diseases has increased during the past 2 decades. 1 DeKruyff R.H. Zhang W. Nadeau K.C. Leung D.Y.M. Wills-Karp M. Summary of the Keystone Symposium “Origins of allergic disease: microbial, epithelial and immune interactions,” March 24-27, Tahoe City, California. J Allergy Clin Immunol. 2020; 145: 1072-1081.e1 Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar The study of the origins of allergy is important to understand the mechanisms of allergy development and to produce interventions to treat or prevent allergic diseases. The term atopic march is used to describe the progression of allergic disease development, beginning with atopic dermatitis (AD) and progressing to food allergy (FA), asthma, and allergic rhinitis. Although it is necessary to focus on early childhood factors, the prenatal environment must also be considered. In particular, factors that contribute to epithelial barrier disruption in the skin, lungs, and gut play a role in the type 2 inflammation associated with allergic diseases. Pollution, other environmental irritants, food chemicals, and allergens are areas of focus that drive allergy development in utero into early childhood.