Check out “What’s New in Research” to find out about discoveries and advancements from Brigham researchers. This month, we feature new research from Brigham researchers on a new model for production of human brown fat cells, the creation of a lipidomic map for insights into immunology, a nasal immunotherpay for Alzheimer’s disase, a new framework for evaluating biomarkers of aging, a new cell therapy for colorectal cancer and more.
New Model for In Vitro Production of Human Brown Fat Cells Lays Groundwork for Obesity, Diabetes Cell Therapy
Brown adipocytes are specialized cells that can use energy to produce heat. This property makes them attractive tools for the treatment of diseases like obesity and type 2 diabetes. Until recently, this therapeutic potential was constrained by limited understanding of how brown adipocyte tissue (BAT) develops from precursors.
A team led by investigators at the Brigham and Women’s Hospital identified a set of cellular signaling cues that lead up to brown adipocyte formation in mice. They then used these cues to develop a protocol that efficiently produced human brown adipocytes in vitro.
The researchers applied a machine learning tool to single-cell RNA sequencing to characterize signals associated with the emergence of different types of tissue in embryonic mice. This analysis revealed a temporary stage of development that precedes BAT formation, marked by high expression of a transcription factor called GATA6. The team verified a similar pattern of expression in human BAT precursors as well.
Reproducing the sequence of signals in human pluripotent stem cells transformed them into brown adipocytes. Further, the researchers demonstrated that these cells were functional — when exposed to stimuli mimicking natural conditions in the body, they responded by increasing metabolism to produce heat. The study provides a model for reliable production of human brown fat cells in vitro.
“There is a growing body of work in preclinical models showing that grafting additional brown fat cells can improve diabetes and obesity,” said corresponding author Olivier Pourquié, PhD, of the Brigham’s Department of Pathology. “Our work could help develop cell therapy strategies for the treatment of cardiometabolic diseases.”
Read more in Developmental Cell.
Researchers Create “Lipidomic Map,” Offering Insights into Immunology
An international team of scientists has developed a method for simultaneously detecting thousands of lipid molecules that are displayed to T cells in the human immune system. The study, co-led by D. Branch Moody, MD, of the Division of Rheumatology, Immunity and Inflammation at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, represents a collaboration among researchers from Oxford, United Kingdom, Melbourne, Australia and Groningen, Netherlands.
The team developed a new and sensitive method to detect more than 2,000 lipids bound to CD1 antigen presenting molecules, which display antigens to the human immune system. While scientists have long known that T cells recognize antigens, until the 1990s, it was thought that these antigens were always peptides derived from proteins. Because lipids are not encoded by genes and are instead made by enzymes and form into membranes, they have entirely different functions and positions in the cell. The ability to measure many lipid antigens at one time will allow future researchers to cross-check any disease-related lipid of interest to the list of candidate lipid antigens from this map and potentially make connections to diseases.
Their efforts yielded the first integrated CD1 lipidomic map, which could help guide the investigation and discovery of lipid blockers and antigens for T cells and support the view that lipids normally influence immune responses.
The research builds on earlier methods that separate cellular lipids in one chromatographic system, which provided only a limited perspective. The new structural biology work, undertaken in the lab of Jamie Rossjohn, PhD, FRS, showed how lipids fit inside proteins using size-based mechanisms. Combined, the structures and biochemistry detail rules about the size, shape, and chemical content of the kinds of lipids that can bind CD1 and cause a T cell response—either activation or deactivation. It is the latest in a series of studies that date back to the 1990s, when Brigham scientists discovered that T cells can recognize lipid antigens.
“I applaud the tenacity of the researchers for building the critical mass of technology needed to develop this multi-stage system that allows large numbers of lipids to be identified, solved individually, and then grouped in patterns,” said Moody. “The Brigham provides an environment where physicians and scientists from differing fields can collaborate. This multidisciplinary effort involved biophysical techniques related to mass spectrometry and biological techniques related to lipid chemistry. The lipids informed immunological outputs, and the mode of lipid recognition is proven through X-ray crystallography.”
Read more in Cell.
Brigham Researchers Find Preclinical Evidence that a Nasal Immunotherapy May Help Treat Alzheimer’s Disease
Alzheimer’s is a debilitating neurodegnerative and neuroinflammatory disease that is difficult to treat. Most existing therapies target the buildup of amyloid beta (Aβ) plaques in the brain, which requires early intervention and intravenous therapy. A team of researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, tested whether a therapy being tested in multiple sclerosis (MS) patients that dampens immune cell inflammation in the brain could have a positive effect in Alzheimer’s mouse models. They found that a nasal immunotherapy—anti-CD3—reduced inflammation and improved cognition independent of Aβ plaques.
In this study, mice were treated three times a week with an intranasal anti-CD3 for five months. The therapy effectively limited the activation of microglia—immune cells responsible for inflammation in the brain. Treated mice performed better in behavioral tests including a water maze, demonstrating improved cognition. Researchers also identified changes in gene expression patterns in the brain and an expansion of regulatory T cells that fight disease in the periphery following treatment. All changes were independent of Aβ plaque levels.
Researchers plan to investigate the use of this immunotherapy in animals in conjunction with anti-amyloid therapies, and expand into human clinical trials. The work builds upon the team’s previous studies testing foralumab—the only fully human anti-CD3 monoclonal antibody treatment—in patients with Covid-19 and MS.
“We provide evidence that intranasal anti-CD3 therapy can dampen microglia activation and expand T cells in a murine model of Alzheimer’s,” said corresponding author Howard L. Weiner, MD, of the Department of Neurology. “This represents a unique approach to treating later-stage Alzheimer’s that can be applied to other inflammatory disease conditions as well.”
Read more in PNAS.
Brigham Researchers Offer Cohesive Framework for Evaluating Biomarkers of Aging
“Aging” can refer to different processes, making it difficult to define a single and highly generalizable molecule or method to measure aging processes. In turn, there are molecular, biological, functional, clinical, and phenotypic biomarkers of aging that lack consistency. Researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, who lead the Biomarkers of Aging Consortium collaborated with experts in aging across the world to systematically adapt and extend existing frameworks to classify biomarkers of aging and their clinical applications.
“As insights into the fundamental biology of aging expand, our work provides a robust framework for the classification and evaluation of biomarkers while documenting challenges and future directions in the field,” said study author Jesse Poganik, PhD, of the Division of Genetics at the Brigham.
Through classifying advantages and limitations of different biomarkers, the team also compiled a list of criteria that allow researchers to determine if a candidate biomarker might be feasible, valid, and useful for a particular context or application. Examples of key criteria for evaluation include age-sensitivity and generalizability across cell types.
“Once validated across different populations and settings, advanced omic biomarkers will equip us with powerful tools to monitor healthy aging, screen for diseases of aging, and identify longevity interventions,” said study author Mahdi Moqri, PhD, also of the Division of Genetics.
The authors also reviewed processes to validate these biomarkers analytically, through reproducible lab measurements, and clinically, through outcomes observed in human research. Finally, they review key challenges for biomarkers to be used clinically, such as differentiating those that assess chronological age from those used to measure rate of aging. They offer a novel framework to prepare a biomarker to advance towards clinical use.
“The ability to quantify biological age and determine how it is affected by interventions is a major advance in the field,” said Vadim Gladyshev, Professor of Medicine, the corresponding author of the article. “It is also critical to define the terms at the heart of what we study, including aging, biological age, biomarker of aging, etc., which may lay the foundation for future advances.” Poganik, Moqri, and Gladyshev are leaders at the Biomarkers of Aging Consortium.
Read more in Cell.
Brigham Researchers Study Immune Cells, Lay Groundwork for Cell Therapy for Colorectal Cancer
Colorectal cancer (CRC) tumors do not respond to major immunotherapies. However, a specific subtype of innate immune cells—γδ T cells—have been associated with improved prognosis for solid tumors including endometrial cancer. A team of researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, set out to study the changes to these tissue-resident immune cells to understand their role and function in different tumor microenvironments. They found differences in the γδ T cell subtypes infiltrating CRC versus endometrial cancer tumors and leveraged this knowledge to develop a cellular therapy that slowed tumor growth in CRC models.
Researchers analyzed tissue samples from 15 patients with CRC, and an additional dataset of 70 patients with CRC, and nine patients with endometrial cancer. The analysis revealed two populations of γδ T cells: one, a cytotoxic population that kills transformed cells and another, a wound healing population. Only the cytotoxic subset was present in endometrial cancer, while CRC samples contained both subsets.
The team found that γδ T cells that reside in the gut play an important role in regular tissue homeostasis but as tumors develop, the wound healing population prevents an appropriate, anti-cancer immune response, and help the tumor grow. The research team used this knowledge to develop a cell therapy protocol to enhance the toxic subset of T cells while suppressing the wound-healing population in CRC solid tumors. Though future research should evaluate any adverse effects of the γδ cell therapy, preliminary findings showed that it could effectively be used to enter peripheral tissue and slow tumor growth in humanized models of CRC.
“We provide an explanation for how the γδ T cells that have an anti-cancer role in endometrial cancer actually contribute to pro-tumor function in the colon microenvironment,” said Lydia Lynch, PhD, of the Division of Endocrinology. “We were then able to propose a cellular therapy for CRC patients to achieve greater tumor clearance. This has broad applications as an ‘of-the-shelf’ cellular therapy for cancer.”
This study was funded by the Brigham IGNITE fund, which advances early-stage discoveries with clinical and commercial potential. Studies like this one show the promise of cell therapy for treating intractable conditions. Mass General Brigham’s Gene and Cell Therapy Institute is helping to translate scientific discoveries made by researchers into first-in-human clinical trials and, ultimately, life-changing treatments for patients. The Institute’s multidisciplinary approach sets it apart from others in the space, helping researchers to rapidly advance new therapies and push the technological and clinical boundaries of this new frontier.
Read more in Nature Cancer.