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The Warren Laboratory is interested in the pathogenesis and treatment of serious bacterial infections, sepsis, and induced secondary inflammation from any cause. Because sepsis is associated with overwhelming stimulation of the innate immune response with tissue damage, we are especially interested in the interactions of the bacterial cell wall with the host and the relationship of microbial clearance to induced inflammation. Our work spans from basic to translational to clinical studies. While new projects are starting all the time, our work has recently become more focused on two thrust areas.
Species Inspired Research for Innovative Treatments (SPIRIT) is an ongoing large scale project in the Warren Lab that aspires to better understand why species respond differently to inflammatory stimuli and infection. We believe that a better understanding of these species differences will permit advances in the translation of results in animal models to human settings and that exploration of the underlying mechanisms could explain heterogeneity of human responses and inspire novel approaches to treat human diseases. For more information about SPIRIT, please go to the SPIRIT section of our site.
A second major thrust area of the laboratory has been to study the role of heme in inflammation. We have learned that red blood cells release hemoglobin in numerous clinical settings, and that cell-free hemoglobin and liberated heme greatly amplify secondary inflammation. We are hopeful that a better understanding of these mechanisms may lead to novel approaches to block potentially damaging inflammation in tissues. For more information about the role of hemoglobin and heme in inflammation and our approaches to block it, please go to the Role of Heme in Inflammation section of our site, under the Research Projects tab.
H. Shaw Warren, MD is an Associate Professor of Pediatrics at Harvard Medical School. In addition, he holds appointments at Massachusetts General Hospital, Shriners Hospitals for Children – Boston, and Spaulding Rehabilitation Hospital. He is also an Associate Faculty member at the Wyss Institute. Dr. Warren graduated from Harvard College in 1973 and Harvard Medical School in 1978. He trained in Infectious Diseases at the Beth Israel Hospital and received further research training at the Dana Farber Cancer Center before doing post-graduate work for three years in the department of Experimental Immunotherapy at the Institute Pasteur, during which time he was supported by a Fulbright Fellowship and then a Mosely Fellowship from Harvard Medical School. He then returned to work at the Massachusetts General Hospital, where he has run a laboratory in the area of host response and inflammation for 25 years.
Dr. Warren is a Fellow of the Infectious Disease Society of America, and member of the American Society for Microbiology, the American Association for the Advancement of Science, Kunkel Society, Massachusetts Infectious Disease Society, and the Pediatric Infectious Disease Society. He has published over 110 articles, book chapters, reviews, letters and editorials relating to inflammation, immunity and infectious disease.
Tian Lin, MD, PhD is an Instructor of Pediatrics at Harvard Medical School. Dr. Lin also holds appointments at Massachusetts General Hospital and Shriners Hospitals for Children – Boston. She received her doctorate in medicine from Tongji Medical University, and she performed her medical residency and practiced Internal Medicine at the Second Affiliated Hospital of Guangdong Pharmaceutical University in China. In 2005, Dr. Lin received her PhD in Microbiology and Immunology from the University of North Carolina at Charlotte. After conducting postdoctoral training in the Department of Pathology at Tufts Medical School, Dr. Lin joined the Warren Lab in 2007.
Dr. Lin has a longstanding interest in host-pathogen interactions in infectious diseases. Her PhD research focused on the host immune response to Salmonella infection. At the Warren Lab, Dr. Lin and her colleagues discovered the synergistic inflammation induced by heme and hemoglobin with multiple microbial TLR agonists and HMGB1, and has been studying hemopexin, a serum protein, as a potential therapeutic reagent to control overactive immune responses in several clinical conditions. These studies were published in many peer reviewed journals and are now the basis for multiple translational research endeavors. Dr. Lin is the principle investigator of the Shriners Hospital for Children grant “Hemopexin suppresses inflammation in burn wounds.” In addition to conducting laboratory research, Dr. Lin teaches preclinical courses at Harvard Medical School.
Frank Riley, MS is the Laboratory Manager for the Warren Laboratory and a Project Manager for the SPIRIT Project. Mr. Riley received a Master of Science in Applied Medical Sciences from the University of Southern Maine in 2010. Mr. Riley studied the affects of serial passaging on adipose-derived mesenchymal stem cells and the role of mitochondrial health in intervertebral disc degeneration before joining the Warren Lab in 2012. Since joining the Warren Lab, amongst other topics, Mr. Riley has studied whether heme-related parameters can be used to predict patient outcome in various secondary infectious diseases such as ARDS, malaria and burns.
The SPIRIT project is an ongoing large scale project in the Warren Lab to better understand why there is such a marked difference in sensitivity of different vertebrate species to many pro-inflammatory stimuli, including bacteria and agonists of most Toll-like receptors. SPIRIT was born out of previous work that Dr. Warren conducted while on sabbatical at the Institut Pasteur in Paris in 2003.
Mice are the most commonly used animal model for the study of inflammatory diseases. However, it has become increasingly apparent that results generated in mouse models reflect human disease poorly. Mice are highly resistant to most inflammatory challenges relative to humans. For example, mice are a million-fold more resistant to a common bacterial toxin, endotoxin, than humans. In addition, certain other vertebrate species, including some primates such as baboons, also evolved high natural resistance to inflammation. These mostly ignored observations seem essential in order to appropriately extrapolate results from studies in animal models to human disease. The failure of animal models to adequately mimic human disease is a major problem for biomedical research and for drug development. As a direct effect, there are costly errors and inefficiencies in the way that research is performed and drugs are developed. The Warren Lab is committed to understanding the reasons for the broad variation that exists across species in regards to inflammatory response.
The ultimate goal of SPIRIT is to take advantage of the innate resilience that some species such as mice have evolved to resist inflammation and to use this information to inspire novel treatment approaches for humans. Our earlier work suggests that one reason that resilient species such as mice can resist high degrees of inflammatory challenge may be that proteins in the plasma of mice re-program and down-regulate immune cells such as macrophages to resist secondary inflammatory toxicity. We are hopeful that this concept might be harnessed to transiently re-program human cells during acute inflammatory states to become resilient to pro-inflammatory stimuli. In essence, the SPIRIT program seeks to take advantage of the inherent resistance of mice and/or other resistant species to lead towards new treatment approaches for humans.
In addition to developing new treatments, SPIRIT may aid in the construction of better animal models of human inflammation. Since current mouse models do not mimic human disease very well because of the large differences in response to inflammation, knowledge on the re-programming of immune cells by mouse proteins to handle inflammation differently than humans should lead to development of more suitable mouse models. Understanding these differences would revolutionize biomedical research and drug and vaccine development. More information about this aspect of SPIRIT can be viewed in Dr. Warren’s TEDMED talk.
Specific research interests within SPIRIT include:
We are exploring the inflammatory sensitivity and resistance of non-rodent species, including members of the primate order such as chimpanzees, baboons, and other primates that are more closely related to humans than mice. By studying primates that differ from humans in innate immune responses, we hope to elucidate mechanisms that might be more directly adapted for human approaches.
SPIRIT is by nature an interdisciplinary endeavor that requires cooperation from experts in several fields of study. Our research overlaps with the fields of genomics, systems biology, primatology, theoretical biology, and others. With this in mind, the Warren Lab is always excited to connect with investigators interested in potential collaboration. If you would be interested in further exploring this potential, feel free to contact Dr. Warren using the contact section of our site.
One early result of the SPIRIT approach is the Warren Lab’s work relating to the role of heme in inflammation. Researchers in our group (together with our collaborators at the Institut Pasteur in Paris) noted that mice respond much differently than humans to endotoxin challenge and that plasma proteins may be involved in their relative resistance. An effort to determine the responsible proteins led to the discovery of a heme-binding protein, hemopexin, which reduces the effects of heme and hemoglobin on macrophages. Although we now believe that hemopexin is not a dominant protein involved in causing the differential resistance of mice and humans to inflammation, we have learned that that extracellular heme may be important in amplifying tissue inflammation in the presence of additional inflammatory stimuli.
In patients with inflamed or necrotic tissues, it is common for microorganisms and degrading blood products to be present at the same time. In this situation, the integrity of red blood cells is lost and hemoglobin is released into the extracellular space. Hemoglobin is a metalloprotein that contains heme (a planar and hydrophobic porphyrin ring containing an iron atom, Fe2+, in the center of the ring). Heme serves as a reversible O2 binding site and redox center and its presence outside of red cell membranes leads to oxidizing injury. Extracellular hemoglobin is rapidly auto-oxidized, spontaneously releasing heme with direct tissue toxicity. We find that while hemoglobin and heme only minimally activate macrophages by themselves, both of these molecules markedly amplify the activation of macrophages when present at the same time as microbial and/or endogenous pro-inflammatory mediators. This finding may explain why the degrading red blood cell contents released after hemolysis or minor trauma or surgery only result in mild inflammation, whereas blood in tissues that is present at the same time as infection causes marked inflammation. The concept that tissue inflammation is driven or amplified by released hemoglobin and heme is a new paradigm.
Our laboratory has found that hemopexin strongly suppresses the amplified inflammatory response. Because this response is synergistic in nature, suppression of the heme component results in large decreases in pro-inflammatory cytokine production from cultured cells. We believe these findings raise the possibility that hemopexin might be helpful as a new treatment that could be used to decrease secondary inflammation in situations where there is rupture and degradation of red blood cells outside of the bloodstream in the presence of a second stimuli, such as microbes.
In order to facilitate translation to human trials it will be important to understand both the molecular mechanisms underlying the synergy and its suppression by hemopexin, as well as other heme-related parameters in relevant clinical settings. Current projects in the laboratory include:
The Warren Lab is currently seeking a project manager to help coordinate the SPIRIT project. This is a large scale, multi-institution project focused on understanding and taking advantage of species differences in innate immunity to develop new strategies to treat inflammation. Please send inquiries to firstname.lastname@example.org.
The Warren Lab is currently seeking a technologist to work on technical aspects of the SPIRIT project. Please send inquiries to email@example.com.
Warren Lab Massachusetts General Hospital - East149 13th StreetCharlestown, MA 02129
The Warren Lab is located in the Charlestown Navy Yard, in the main research building of Mass General. The address is 149 13th Street, Charlestown, MA 02129. Our building is sometimes referred to as MGH East, and is on Boston Harbor, very close to the USS Constitution. We are a 15 minute shuttle bus ride away from the main Mass General campus in Boston.
Please note: Once you arrive at the building, if you do not have a Mass General security badge, you must check in at Security Desk for a temporary pass and an escort.
Parking is available at the parking garage adjacent to 149 13th building.
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