Nutrient, Genetic, and Metabolic Research
Nutrient, Genetic, and Metabolic Research
The Decade of Discovery 2021 Annual Report
NUTRIENT, GENETIC, and METABOLIC RESEARCH
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Letter from Gökhan S. Hotamışlıgil, MD, PhD The Sabri Ülker Symposium Next Generation of Scientists Gökhan S. Hotamışlıgil and Refik Anadol Collaboration Looking Forward
THE DECADE OF DISCOVERY
The Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research is dedicated to advancing and expanding scientific understanding of the fundamental mechanisms of chronic metabolic diseases and their intricate relationship with human health and disease. Despite the multitude of challenges presented by the pandemic, our Center continues its vital activities. Our third “Metabolism and Life” Symposium was the highlight of the year with record attendance from around the globe, which allowed us to continue our pursuit of scientific progress to combat metabolic diseases. We were happy to see the strengthening of our technological platforms with the outfitting of the Sabri Ülker Center Advanced Physiology Lab and through the expansion of its capabilities. With a year of experience utilizing this sophisticated instrumentation, the complexity of metabolic experiments enabled by this generous donation of cutting-edge equipment by the Ülker family has brought our understanding of physiology to new levels. Our optimism can only be tempered by time, while our energies are not dampened by the constraints of the pandemic environment.
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Art and science present ideas about the world...
...that render forms, connections, and answers.
Art and science are important to...
...understanding the universe and our place within it.
“ Science is ever more important for the welfare of humanity. Yet, we are experiencing the greatest challenges to its performance, dissemination, translation, and acceptance at a time where revolutionary opportunities emerge from life sciences and humanity is at its greatest need. Sabri Ülker Center allows us to pursue our most ambitious long-term scientific goals, vigorously and without interruption. We train the next generation of scientists to be bold, follow the science where it leads, and focus on the greatest health challenges with an eye on the impact. We are most grateful for this invaluable privilege and are motivated to pursue fundamental, as well as translational, science and contributions to the well-being of humans around the world.”
DEAR FRIENDS,
“ Scientific discovery takes far more than the occasional flash of brilliance, as important as that can be. Usually, it takes time, hard work, and patience. It takes training and requires support from others. But it holds a promise like no other area of human endeavor.”
I am pleased to report we have made great progress in returning to some variation of ‘normal’ this past year. The adjustments we were able to make in 2020, as a result of the profound effects of COVID-19, have enabled this progress to be made in the latter half of 2021. Worldwide suffering continues with the inability to administer vaccines in significant proportions in many countries, in addition to already existing economic and health care challenges. Travel constraints have affected the mental health of many in science—a field known for the collaboration of people from every country. Many of us have not seen our families in person for an extended period and suffered the loss of loved ones. Despite these issues, our laboratory strives to maintain a positive community feeling—one of mutual respect, compassion, and support—all the more essential during these difficult times. I continue to acknowledge the tremendous value in the efforts made by members of our scientific community in seeking new strategies to maintain and strengthen the international bonds of collaborative research. We appreciate how fortunate we have been to be able to continue our efforts vigorously, as we strive to ease the suffering caused by metabolic diseases. In May, as the result of a truly outstanding effort by our colleagues in the Sabri Ülker Foundation, we were able to host the 2021 Sabri Ülker Annual International Symposium on Metabolism and Life in a hybrid event. Later in this report, I will give you a view of how this effort was successfully designed and implemented. With speakers from almost every continent, some present in İstanbul, and others speaking from their home laboratories, a record number of international guests were able to stream the symposium live, in both Turkish and English. This report will offer summaries of the presented talks, as well as the opportunity, using a QR reader, to view and listen to some of the recordings from the symposium. This year was also an important one for major scientific achievements made by the Center’s scientists, as several critical manuscripts are now at the publication stage. The findings of these studies will be discussed in more detail in our upcoming report, which will highlight the discovery of a new hormone and mechanism of hormone action, mechanisms underlying inflammation and how they emerge and disrupt the function of fat cells, and how molecular structures of the cells are central for metabolism. We were also thrilled to see our work “Molecular Architecture”, in collaboration with Refik Anadol, featured in the Venice Biennale. Metabolism also emerged as a critical determinant of the course of infectious diseases, most importantly the severity and human mortality caused by the Sars-CoV-2 virus. Our scientists are also exploring novel pathways to limit the damage and death from Covid-19 by exploring metabolic vulnerabilities of the virus towards novel preventive and therapeutic strategies. The continued support of the Ülker family has made all this possible, despite the significant constraints caused by the pandemic. It is essential that, despite all of the current constraints, we continue our efforts, unabated, to make progress in our ongoing fight against the greatest threats to global human health— metabolic diseases. The intellect and creativity of our laboratory members and colleagues from other institutions, leveraged by the support of the Sabri Ülker Foundation, enable the Sabri Ülker Center to unceasingly strive to make discoveries and advance the science with the ultimate goal of improving the health and well-being of people throughout the world.
Gökhan S. Hotamışlıgil, MD, PhD
Director of the Sabri Ülker Center for Nutrient, Genetic, and Metabolic Research James S. Simmons Professor of Genetics and Metabolism at the Harvard T.H. Chan School of Public Health
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•LIVE
SABRi ÜLKER CENTER SYMPOSIUM May 25–26, 2021
SCAN HERE
Visit the 2021 Sabri Ülker Center Symposium website.
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THE SABRi ÜLKER SYMPOSIUM
The Sabri Ülker Symposium, “Metabolism and Life,” organized by the Sabri Ülker Center for Metabolic Research at the Harvard T.H. Chan School of Public Health, was a scientific and cultural celebration. The hybrid event was held on May 25-26, 2021 in İstanbul, Turkey, and drew audiences from around the world. The program featured highly innovative research on metabolism, which is the most fundamental process of life. Continuing with the symposium’s long-running theme of merging art and science, the event featured two performances by Burcu Soysev of the İstanbul State Opera. The symposium’s scientific panels began with the younger generation of researchers – the “Rising Stars” – and continued with talks by leaders in the field of metabolism. Speakers discussed cutting-edge research on metabolism in the context of cancer, immunity, brain function, obesity, and nutrient management in health and disease. Following a keynote address by Nobel Laureate Roger Kornberg of Stanford University on the roles of nucleosomes and chromosomes in the fundamental operations of gene expression machinery, Dr. Elif Firat-Karalar was announced as the 2021 Sabri Ülker Science Award winner. Dr. Firat-Karalar gave an exciting research talk on cellular diversity, and then discussed the crucial roles that mentors, family, and society play in the lives of women leaders in science. The event ended with closing remarks by Sabri Ülker Center Director Dr. Gökhan Hotamışlıgil, who reminded the audience that encouraging young scientists today is essential for the long-term victory of truth over ignorance, and science over misinformation.
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THE POWER OF SCIENCE, ART, AND PHILANTHROPY
Ali Ülker Sabri Ülker Foundation
A video presentation illustrated the many scientific contributions, which have been made possible by the support from the Sabri Ülker Foundation and through the Center’s activities. Ali Ülker then took to the podium to welcome scientists and colleagues from around the world. He underscored the importance of science and the role of universities during the challenging conditions created by the coronavirus pandemic. “It is now abundantly clear that science is vitally important for mankind’s existence,” stated Ülker. “Even if our current society doesn’t see the benefits of today’s scientific endeavors, future generations will.” Ali Ülker expressed that a well-run society is one that makes decisions based on facts and science. He looked ahead to the foundation’s ongoing cooperation with Harvard to pave the way for more discoveries and expressed excitement in being able to support the advancement of science.
The symposium opened with remarks from Ali Ülker, on behalf of the Sabri Ülker Foundation and Family, who emphasized the importance of scientific knowledge and research, and expressed gratitude to all speakers, organizers, and participants for making this event possible.
As is the tradition of the Sabri Ülker Center’s Symposium, art was again part of this year’s event. The meeting featured a riveting opera performance by Mrs. Burcu Soysev of the İstanbul State Opera. At the opening session, Mrs. Soysev stated that participating with her art in such an extraordinary scientific event will be a most special memory. She then delivered an extraordinary and heartwarming rendition of an Anatolian folk song from master Neşet Ertaş. Her performance was so powerful that for those few moments, we all forgot about earthly concerns and anxieties. Mrs. Julide Ates, a renowned broadcaster and the MC for the symposium, then introduced the Center’s Director, Dr. Gökhan Hotamişligil. In his speech, he emphasized that “science and art have the power to unite, overcome divisions, heal, and bring about peace and harmony. Science, in particular, can have an enduring power and we must do all we can to support and disseminate science, as this is the only insurance policy we have for our future.”
Burcu Soysev İstanbul State Opera
SCAN HERE
Listen to the performance by Burcu Soysev. 11
KEYNOTE ADDRESS
CHROMOSOME STRUCTURE AND TRANSCRIPTION Roger Kornberg, PhD Stanford University
The symposium’s keynote address was delivered by Dr. Roger Kornberg, who received the Nobel Prize in Chemistry in 2006. He is the Winzer Professor of Medicine at Stanford University, and his work has been instrumental to the fields of chemistry and molecular biology. In his keynote address, Dr. Kornberg focused on chromatin, transcription, and chromosomal structure. Research has shown that nucleosomes serve as general regulators of gene expression. To clarify the role of nucleosomes in transcription, Dr. Kornberg’s group performed a series of studies showing that chromatin may interact with transcription proteins. Further experiments indicated that a nucleosome can serve as a component of the transcription-initiation complex, and can even enhance this process. Dr. Kornberg is also interested in the chromosome structure and mitotic chromosomes. Mitotic chromosomes generally appear the same, despite the underlying chromatin fiber having a highly variable composition. Thus, macroscopic order is imposed on microscopic disorder. To investigate the forces responsible for condensation, Dr. Kornberg’s group measured individual chromosomes and directly imaged chromosomal material to discover a scaffold. Additionally, by applying automated procedures, his group obtained thousands of images reflecting the cycle of condensation and de-condensation in individual chromosomes. Their work demonstrates that chromosome condensation is reversible, indicating that the memory of morphology must reside in the central filament. Thus, the cylindrical shape of the mitotic chromosome can be simply explained by condensation of the chromatin against the central axis. These findings on nucleosome function and chromosomal structure provide novel insights into the fundamental operation of gene machinery, which is critical in the operation of all cells.
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SABRi ÜLKER INTERNATIONAL SCIENCE AWARD WINNER
Dr. Elif Nur Firat-Karalar of Koç University received the 2021 Sabri Ülker Science Award. Upon receiving the award, Dr. Firat-Karalar expressed gratitude to the Sabri Ülker Foundation as well as her colleagues, collaborators, mentors, and family. She stated that the guidance from three of her mentors in particular have played key roles in her research career. Specifically, her doctoral advisor who modeled hard work and professionalism, as well as her post-doctorate mentor who taught her to fearlessly ask questions. And third, her most recent mentor, Dr. Monica Bettencourt-Dias, a positive role model for women in science who showed Dr. Firat-Karalar how to build an internationally recognized research program in a developing country. Dr. FiratKaralar’s research focuses on how diversity arises from molecular interactions in order to answer the following questions: How do cells assemble and maintain dynamic cellular compartments? How do microtubules assemble into cilia, flagella, centrioles, and mitotic spindles? How can a single structure, when mutated, cause a wide range of disorders? By addressing these fundamental questions, Dr. Firat-Karalar hopes to elucidate the pathogenesis of ciliopathies, which are rare developmental disorders caused by abnormalities in cilia. Ciliopathies are characterized by
metabolic and developmental impairments and can lead to retinal degeneration, retardation, obesity, and diabetes. Dr. Firat-Karalar’s overarching research vision is to gain a molecular understanding of cellular diversity by clarifying the biology of membrane-less structures, and to ultimately develop therapies for ciliopathies. In an informal round-table discussion, Drs. Hotamışlıgil and Firat-Karalar discussed ways to empower women leaders in science. Dr. Firat-Karalar described how her mother was an early supporter of her career ambitions and modeled multitasking and a strong work ethic. Dr. FiratKaralar is currently mentoring younger scientists through public disseminations, presentations, and being a role model for women in science. Drs. Firat-Karalar and Hotamışlıgil agreed on the urgent need for numerous essentials such as flexible working hours and onsite childcare, which are factors that can help turn individual success stories into societal successes, by having society-level interventions to support women leaders in science. 13
SABRi ÜLKER SYMPOSIUM SPEAKERS
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David Mangelsdorf, PhD
Anu Suomalainen, MD, PhD
University of Texas Southwestern Medical Center
University of Helsinki and University Hospital
Dr. David Mangelsdorf is a Professor in the Department of Pharmacology at the University of Texas Southwestern Medical Center. His group investigates the role of fibroblast growth factor 21 (FGF21) in pancreatitis, a debilitating and sometimes lethal disease involving inflammation of the pancreas. The pancreas synthesizes and secretes digestive enzymes in response to feeding cues. FGF21 helps maintain homeostasis in the pancreas and protects against proteostasis and proteotoxicity. To elucidate the role of FGF21 in pancreatitis, Dr. Mangelsdorf’s lab developed three mouse models of pancreatitis that fully recapitulate the disease in humans. In one model, they administer cerulein – an oligopeptide that stimulates pancreatic secretion – to mimic the sequelae of the disease. In the second model, the group mimics alcohol-induced pancreatitis by administering two injections of alcohol and fatty acid. Finally, the third model utilizes endoscopic retrograde cholangiopancreatography, a routine medical procedure that can lead to pancreatitis in a small portion of patients. In all three models, pancreatitis leads to edema, inflammation, and necrosis. Dr. Mangelsdorf’s group demonstrated that the FGF21 treatment completely resolves symptoms in all models within 24 hours. These findings suggest the possibility of pancreatitis treatment, based on FGF21 as a replacement therapy. Dr. Mangelsdorf has demonstrated another approach to increase FGF21 through the use of the protein kinase R-like ER kinase (PERK) inhibitor, which rescues endogenous FGF21 levels in mice and reverses pancreatitis.
Dr. Anu Suomalainen is a Professor at the University of Helsinki. Her overarching goal is to understand mitochondrial disorders, in order to improve diagnoses and develop therapies. Mitochondrial disorders are highly tissue-specific, can be devastating and progressive, and have no cures. These disorders can range from neonatal fatal multisystem disorders to diabetes, neurodegeneration, and tumorigenesis. In adults, mitochondrial dysfunction commonly affects muscles. Dr. Suomalainen’s team generated deletor mice to replicate the key components of adult-onset mitochondrial disease. These mice showed upregulation of the gene MTHFD2 and activation of ATF5, reflecting a mitochondrial stress response conserved in humans and mice. Dr. Suomalainen’s group found that a primary mitochondrial insult can remodel cellular biosynthesis in the muscles and heart. Similar metabolic responses exist in both mitochondrial disease muscles and proliferating cancer cells, potentially due to the activation of mTOR. Dr. Suomalainen’s team found that an mTOR inhibitor rescues the stress response elements of the muscle, and can even reverse disease progression. Dr. Suomalainen’s team recently treated mice with an NAD+ vitamin B3 booster, which rescued morphological changes in the muscle. When patients with mitochondrial myopathy were administered an NAD+ booster (niacin), they exhibit: 1) a remarkable and long-lasting increase of NAD in the bloodstream; 2) a marked decrease in liver and visceral fat; and most importantly, 3) a strong improvement of muscle strength. Thus, niacin is an efficient NAD+ booster, which can rescue function in mitochondrial muscle disease.
Christopher Glass, MD, PhD University of California San Diego
Dr. Christopher Glass is a Professor of Cellular and Molecular Medicine at the University of California, San Diego. His lab uses transcriptional enhancers to decode myeloid cell diversity in liver disease. In the liver, macrophages, known as Kupffer cells, are crucial for iron homeostasis. By exploiting dynamic enhancer landscapes and chromatin immunoprecipitation sequencing, Dr. Glass’s group has investigated the development of macrophage diversity in non-alcoholic fatty liver disease. Dr. Glass and his colleagues found that Kupffer cells change in a nonalcoholic steatohepatitis (NASH)diet mouse model, which is characterized by liver inflammation and damage caused by a buildup of fat in the liver. In this model, the Kupffer cells transition from healthy to sick, corresponding to a transition from a healthy liver to a liver suffering from NASH. Glass’ lab developed a method for sorting healthy and NASH liver cells, enabling the team to find convergent and divergent patterns of gene expression associated with diet and location. In particular, they observed the upregulation of two populations of macrophages—TREM2 and CD9—that have been linked to metabolic and neurodegenerative diseases. Thus, at the cellular level, the transition from a healthy liver to a diseased NASH liver is associated with phenotypic changes in Kupffer cells. These and other findings from the Glass lab have shed light on the role of macrophage phenotypes in liver disease, which is valuable for advancing our overall understanding of health and disease.
RISING STAR
Betül Kaçar, PhD University of Arizona
Dr. Betül Kaçar is an Assistant Professor of Molecular and Cellular Biology at the University of Arizona. Two primary questions drive Dr. Kaçar’s work: 1) Are we alone? 2) How did life on Earth begin? Prior to the origin of life, approximately 3.5 billion years ago, the Earth gave rise to chemicals like lipids and amino acids, which exhibited networks, chemical structures and reactions, without requiring biology. However, it is unclear how this chemical evolution led to the first biological cell. This inquiry is at the heart of Dr. Kaçar’s investigations. Dr. Kaçar and her colleagues are attempting to create a chemical network with properties comparable to those of a living system, and one that can dynamically respond to its environment. Using a radioactive chamber, her group radiated a chemical mixture and found that these building blocks could work together to exhibit biological behaviors. The group’s next step is to produce a system that can dynamically respond to its environment. This work is highly valuable, as the ability to produce a chemical system with biological properties can lead to promising applications. For example, this line of research may enable scientists to generate computers that use chemicals instead of digital materials. Dr. Kaçar’s lab also seeks to understand whether life must rely on a highly constrained network architecture, and whether a prebiotic chemistry will always lead to the same biological outcome, thus addressing the fundamental question of whether biology must be constrained to life as we know it.
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SABRi ÜLKER SYMPOSIUM SPEAKERS
Judith Klumperman, PhD
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Jeffrey M. Friedman, MD, PhD
University Medical Center Utrecht
Rockefeller University
Dr. Judith Klumperman is a Professor of Cell Biology at the University Medical Center Utrecht. Dr. Klumperman’s group applies novel imaging techniques to study lysosomes, which are organelles responsible for breaking down macromolecules. Over the past 10 years, research has shown that the lysosome also controls cellular metabolism by sensing the nutrient state. When sufficient nutrients are available, growth is induced. Without sufficient nutrients, the machinery changes and leads to autophagy, a natural process in which cells degrade any damaged or unnecessary components. Multiple microscopy approaches are available for imaging the lysosomal system, however, each approach requires different samples. To combine the existing approaches, Dr. Klumperman’s group uses a method called correlative light and electron microscopy (CLEM), which makes it possible to acquire both ultrastructural and cellular information. Dr. Klumperman has applied CLEM to image lysosomal compartments and molecular regulators. These regulators include the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, which is required for lysosomal fusion events. Through a series of innovative studies, Dr. Klumperman’s research team demonstrated that the absence of HOPS compromises endocytic trafficking to lysosomes, leads to autophagosome accumulation, and causes changes in the lysosomal morphology. Thus, the absence of HOPS mimics starvation and lysosomal stress. These findings shed light on the underlying machinery of lysosomes and how cells adapt to different nutritional and metabolic states.
Dr. Jefferey M. Friedman is a Professor at Rockefeller University and an Investigator at the Howard Hughes Medical Institute. His landmark discovery was identification of leptin, a hormone made by fat tissue that plays a fundamental role in appetite and body weight. Although most people believe that obesity is caused by overeating, Dr. Friedman discovered that overeating and weight gain can be caused by the absence of leptin or its receptor. When genetically obese and normal mice are treated with leptin, they reduce food intake and expend more energy. Dr. Friedman illustrated the power of leptin with a dramatic case study: A child with normal birth weight became morbidly obese during infancy. He overate, had high insulin levels, and weighed 90 pounds at the age of four. The child’s inbred pedigree suggested an underlying genetic issue—Dr. Friedman discovered that the child’s body could not produce leptin. When treated with leptin, the child lost weight and started eating an age-appropriate number of calories. This case report demonstrates that obesity is a biological and genetic disorder. Dr. Friedman’s group is currently investigating the pathways that adjust leptin production in response to changes in fat cell mass. He presented findings on the neural networks that respond to Leptin. Recently, the group found that chronic, but not acute, doses are needed for the beneficial effects of leptin. Paradoxically, although feeding is a binary behavior, it is activated by numerous pathways that process different sensory information. The Friedman research team ultimately hopes to understand how a single molecule like leptin regulates a complex, yet binary behavior like feeding.
RISING STAR
Nilay Yapıcı, PhD Cornell University
Nilay Yapıcı is an Assistant Professor of Neurobiology and Behavior at Cornell University. Dr. Yapıcı and her colleagues seek to understand how the brain regulates food intake. The brain integrates stimuli, such as smell and taste, with internal metabolic signals generated by the gastrointestinal tract and other cells to regulate how an animal consumes food. Problems arise when the brain cannot appropriately control food intake, which can lead to metabolic imbalances and obesity. Dr. Yapıcı’s group studies the dynamics of food ingestion by using fruit flies as a model system. Their recent work identified neurons that are necessary for ingestion, which are located in the taste-processing center of the fly brain. When the activity of these neurons is genetically inhibited, the flies consume very small amounts of food, even if they are hungry. By imaging the activity of these neurons in the fly brain, Dr. Yapıcı’s group found that the neural activity is modulated by sugar concentration and metabolic status. Using optogenetics, they demonstrated that sugar-sensing gut neurons stimulate ingestion neurons in the brain. Dr. Yapıcı hypothesizes that these neurons communicate with the brain, and transform sugar information in the gut to the brain circuit to regulate the perception of food and food intake. Her findings also suggest that sensing of sugars in the gut may further promote sugar ingestion, elucidating a direct line of communication between the gut and the brain. This work has important implications for obesity, as interfering with gut–brain connections in humans might help regulate sugar intake, thus providing an alternative approach for obesity treatment.
Tobias Walther, PhD Harvard University
Dr. Tobias Walther is a Professor of Molecular Metabolism at Harvard University. Dr. Walther’s lab seeks to understand how organisms operate under energy fluctuations. Because energy sources and needs vary over time, organisms have evolved the ability to temporarily store metabolic energy, primarily in the form of lipids. In the cell, lipid droplets form an organic oil phase that is separated from the aqueous phase by emulsifiers and surfactants. This situation presents a fundamental problem for cells—oil provides an extremely compact way to store metabolic energy, but the aqueous phase is where life happens. In this context, Dr. Walther’s group has investigated how cells generate the oil phase, and how proteins localize on lipid droplets to mediate metabolism. His lab has made important discoveries regarding an enzyme critical for oil generation called DGAT1, including solving the enzyme’s structure, and elucidating a mechanism by which this enzyme incorporates triacylglycerol to produce oil. Dr. Walther’s lab has also uncovered a complex between the molecules seipin and LDAF1 that organizes lipid droplet formation by associating it with triglycerides. Dr. Walther’s group has also found that proteins localize to lipid droplets via two pathways – one in which proteins are targeted from the cytosol to the lipid-droplet surface; and one in which proteins are inserted into the endoplasmic reticulum, and then migrate to the droplet surface. These novel findings provide valuable insights into the basic mechanisms governing the formation and usage of lipid droplets in cells, and how this organelle responds to meet the metabolic demands.
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SABRi ÜLKER SYMPOSIUM SPEAKERS
Peng Li, PhD Tsinghua University
Dr. Peng Li is a Professor in the School of Life Sciences at Tsinghua University. Dr. Li’s research includes the study of lipid droplets in the context of obesity. Lipid droplets are important organelles that mediate lipid storage, obesity development, phospholipid exchange, protein storage, viral infection, and autophagy. Uncontrolled growth of lipid droplets is a major issue in obesity and other metabolic diseases. Dr. Li’s lab has found that Cidea and Cidec – two members of the cell deathinducing DFF45-like effector (Cide) protein family – are important for regulating lipid storage and insulin deficiency in mice. Dr. Li and colleagues performed a series of elegant studies on various members of the Cide family to explore how they behave in normal vs. high-fat diet conditions. These studies revealed that Cide proteins are important for controlling lipid homeostasis and size of lipid droplets. Dr. Li has dissected this pathway, and discovered that lipid droplets work with microtubules to move and contact each other, forming a complex in the presence of members of the Cide family that can interact with each other. Dr. Li’s group also found that certain mutations in Cide proteins can disrupt oligomerization. Moreover, the group demonstrated that the N-terminal region of Cide proteins plays a key role in lipid transfer and lipid droplet fusion, two processes that are essential for lipid metabolism. This work provides novel insights into the mechanism controlling energy management in cells and how these contribute to obesity and metabolic disease.
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RISING STAR
Semir Beyaz, PhD Cold Spring Harbor Laboratory
Dr. Semir Beyaz is a Cold Spring Harbor Laboratory Fellow and Donaldson Trust Translational Fellow. His research focuses on nutrient-gene interactions in cancer and immunity. All organisms need nutrients to live and grow. However, imbalances between nutrient intake, storage, and expenditure can have serious consequences. Indeed, we are facing a rise in adult and adolescent obesity that threatens global health in the decades ahead by triggering an array of metabolic diseases, as well as other diseases including cancer. Dr. Beyaz and his research team are focused on uncovering the links between obesity and cancer. Dr. Beyaz’s early work found that a high-fat diet can allow stem cells to acquire mutations which cause cancerous tumors. This work demonstrated that obesity can affect one’s risk of developing cancer. Dr. Beyaz and his colleagues are currently investigating how dietary changes influence the ability of the immune system to identify and destroy tumor cells. Exciting new research suggests that diet-induced obesity can influence intestinal immune cells and tumorinitiating stem cells. Using cutting-edge molecular approaches, the Beyaz lab recently found that a highfat diet can initiate a cascade of events, which ultimately increases the incidence of tumors. Dr. Beyaz is now exploring specific microbes in the intestine that are particularly affected by a high-fat diet. The Beyaz lab is actively developing innovative models to illuminate the links between nutritional alterations, cancer, and immunity.
Gisou van der Goot, PhD Swiss Federal Institute of Technology Lausanne
Dr. Gisou van der Goot is the Head of the Laboratory of Cell and Membrane Biology at the Swiss Federal Institute of Technology Lausanne. Dr. Van der Goot’s lab investigates the connection between lipid metabolism and severe acute respiratory syndrome (SARS) infection. In particular, they have shown that the Spike protein – a key component of the SARS coronavirus 2 (SARS-CoV-2) virus – is a substrate for palmitoylation. Palmitoylation is a reversible lipid post-translational modification that can modulate all stages of cell function, and facilitate the formation of protein-to-protein complexes. Dr. van der Goot’s group discovered that Spike palmitoylation is rapid and efficient. They then investigated the role of Spike palmitoylation in viral assembly and infection, and found that palmitoylation protects Spike from the endoplasmic reticulum-associated degradation pathway, which in turn promotes Spike expression. By quantifying contacts between the transmembrane domain and lipids, Dr. van der Goot’s group observed that the cytosolic side of the membrane prefers to interact with lipidordered domains, indicating that the virus induces lipid asymmetry. The group also demonstrated that Spike redistributes to detergent-soluble membranes. Interestingly, the SARS-CoV-2 virus induces detergent resistance, and Spike palmitoylation promotes infectivity through viral lipid composition. These findings explore how the pathogen and host cell machinery interacts and suggest a potential therapeutic target for SARS, other coronaviruses, and envelope viruses.
Takashi Kadowaki, PhD University of Tokyo
Dr. Takashi Kadowaki is a Professor in the Department of Prevention of Diabetes and Lifestyle-Related Diseases at the University of Tokyo. Dr. Kadowaki investigates the molecular mechanisms underlying obesity-linked insulin resistance and type 2 diabetes. His group demonstrated that chronic hyperinsulinemia in obesity decreases the expression of insulin receptor substrate 2 in specific macrophages in mice. This, in turn, causes inflammation, gluconeogenesis, and insulin resistance. Dr. Kadowaki’s group also investigated the role of adiponectin and its receptors (adiponectin receptor 1 and 2) in obesity-linked insulin resistance and type 2 diabetes. Adiponectin is a fat-specific hormone that is abundant in white adipose tissue. Reduced levels of plasma adiponectin, caused by genetic and/or environmental factors, can contribute to the development of insulin resistance, type 2 diabetes, and atherosclerosis. Dr. Kadowaki’s group demonstrated that adiponectin receptor 1 exerts anti-inflammatory actions in macrophages, and adiponectin receptor 2 contributes to the anti-atherosclerosis actions of adiponectin. Caloric restriction, exercise, and the adiponectin pathway—all activate pathways that can suppress diabetes and cardiovascular disease, and increase life expectancy. Dr. Kadowaki’s group has developed an adiponectin receptor agonist called AdipoRon, which mimics caloric restriction/exercise. In mice, AdipoRon increases insulin sensitivity, normalizes glucose and lipid metabolism, increases energy dissipation, blocks inflammation, and promotes healthy longevity. Thus, AdipoRon may serve as a first-in-class drug for obesity-linked diseases, aimed at improving healthy longevity.
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SABRi ÜLKER SYMPOSIUM SPEAKERS
Satchidananda Panda, PhD Salk Institute
Dr. Satchidananda Panda is a Professor in the Regulatory Biology Laboratory at the Salk Institute for Biological Studies. Dr. Panda has advanced a circadian theory of health, based on time-restricted eating for reducing the burden of metabolic diseases. Circadian rhythms are regulated by a central biological clock in the hypothalamus, which interacts with sleep, nutrient metabolism, and physical activity under the control of light and darkness. If presented at the wrong time, food— instead of the brain—becomes the master regulator of the circadian rhythm. To investigate the importance of the timing of eating, Dr. Panda’s group has compared mice that received either ad libitum feeding or timerestricted feeding. The two groups consumed the same number of calories, but the time-restricted group showed lower body weight, cholesterol, and blood sugar, increased energy expenditure, motor coordination, and endurance, as well as healthier livers. Dr. Panda’s group also found differences in the effects of a time-restricted diet based on sex, with females showing lower body fat reduction compared to males. For human studies, Dr. Panda’s group has created an app—mycircadianclock. org—to track feeding times. The team found that 50% of adults eat over a 14-hour period. When participants enlisted in a 10-hour time-restricted eating schedule for 12 weeks, they reported a marked improvement in sleep, and diabetic participants reported near normal glucose levels. Thus, time-restricted eating optimizes one’s circadian rhythm, which can positively impact many of the chronic diseases which plague our society.
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RISING STAR
Gülçin Pekkurnaz, PhD University of California San Diego
Dr. Gülçin Pekkurnaz is an Assistant Professor of Neurobiology at the University of California, San Diego. Her lab investigates the molecular mechanisms underlying brain function. Mitochondria generate most of the energy in the brain, wherein mitochondria must work properly within the complicated shape and size of neurons. Mitochondria must also be capable of motion, sensing nutrient availability, and providing energy to cells to maintain a healthy equilibrium. Defects in mitochondrial function can lead to brain disorders such as age-dependent neurodegeneration, cognitive decline, psychiatric syndromes, migraines, and visual impairment. Dr. Pekkurnaz’s lab studies the mechanisms underlying metabolic homeostasis in synapses. They are currently exploring two lines of inquiry: 1) how neurons control mitochondria and metabolism; and 2) how different types of neurons reprogram mitochondria to suit their unique functions. Dr. Pekkurnaz and her colleagues recently demonstrated that glucose, the major fuel source of the brain, can act as a signaling molecule through a metabolic pathway called the hexosamine biosynthetic pathway. A metabolic sensor constantly reads and transmits glucose flux information to substrate proteins. Changes in glucose levels in the blood can lead to changes in glucose levels in the brain. Therefore, glucose can act as a signaling molecule. Dr. Pekkurnaz’s group has isolated the process that is crucial for increasing energy production in the brain. Given that perturbations in metabolic sensing can lead to intellectual instability and cognitive decline, these discoveries have important implications for brain function and brain disorders.
INVITED LECTURES AND HONORS Gökhan S. Hotamışlıgil, MD, PhD March 2021 Georgetown University Dean’s Seminar Series Presentation, Georgetown University, Washington, DC April 2021 Keynote Lecture, International Rotary Foundation. The New Frontier of Biomedical Research. Virtual
David Sabatini, MD, PhD Massachusetts Institute of Technology
Dr. David Sabatini is a Professor of Biology at Massachusetts Institute of Technology, a Member of the Whitehead Institute, and an Investigator at Howard Hughes Medical Institute. He studies the molecular pathways that regulate metabolism. Dr. Sabatini’s group is currently investigating the food signals that activate the mTOR pathway, which link an animal’s growth to its nutritional state. In a series of in vitro experiments, Dr. Sabatini’s team observed human cells within media that completely lacked amino acids. When amino acids were added into the media, the mTOR complex 1 (mTORC1) quickly localized to the lysosomal membrane. Dr. Sabatini’s group recently showed that a leucine-free diet inhibits mTORC1 in mice, which highlights the notion that our systems can detect the absence of a single critical amino acid. In a similar vein, knockout mice placed on a leucine-free diet continuously lose weight, an effect that can be rescued by an mTOR inhibitor. Dr. Sabatini’s group has recently begun experimenting with fruit flies. Fruit flies are attracted to rotting fruit because microorganisms, such as fungi, make amino acids with the ammonia contained in the fruit. The research team offered flies either plain or leucine-laced apple slices. Although the flies initially avoided the leucine-laced slices, they came to prefer these slices over the next 6-24 hours, suggesting learning over time. Dr. Sabatini postulates that leucine-sensing may affect the reward circuit in the brain. Hence, flies feel rewarded when they eat leucine-laced apple slices, which in turn impacts feeding and egglaying behaviors. In future work, the Sabatini lab hopes to elucidate how glial cells relay leucine-related information to neurons.
May 2021 Exhibitor, “Molecular Architecture”, joint exhibit “Sense of Space” with Refik Anadol Studios, Venice Biennale Architecture, Venice, Italy Keynote Lecture, Endocrine Society Meeting, Israel “Conversations with Ashish Jha, Dean, Brown School of Public Health - Basic Science and Impact on Public Health” June 2021 Keynote Lecture, Trans-National Institutes of Health “Metabolic Regulation of Inflammation and its Resolution”, Washington, D.C. Received Doctor of Medicine and Philosophie Honoris Causa Ankara University, Ankara, Turkey August 2021 Diabetes Virtual Summer Camp 2021, eLecture September 2021 Dean’s distinguished lecture, Koc University Medical School, Istanbul October 2021 Keynote lecture, 15th Annual Graduate School Meeting “Beyond the barriers: New perspectives and advances in life sciences” Muenster, Germany November 2021 Student Invited Speaker, Perelman School of Medicine, University of Pennsylvania, Closing Keynote Lecture, 1st International Pharmacology Congress, Turkish Pharmacology Association
Hatoon Baazim, PhD November 2021 Invited speaker: Science communication initiative to educate school children about vaccines and immunology; Arabic panel discussion, Austrian Red Cross
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THE SABRi ÜLKER SYMPOSIUM: CLOSING REMARKS
I would like to take this opportunity to commend the team from the Sabri Ülker Food Research Foundation, for a truly exceptional effort that made our symposium possible. Facilitating sophisticated communication technologies, they produced a seamless virtual experience that enabled audiences throughout the world to participate this year. We certainly missed the warmth and intellectual stimulation of engagement made possible by gathering in one location. However, the virtual broadcast offered a delightful firsthand opportunity to share groundbreaking science on the molecular underpinnings of metabolism, its interaction with nutrients, and its dysregulation in chronic diseases. As is tradition, the symposium was focused on many different aspects of metabolism, which encompasses all of the reactions that generate and use energy, and is the most fundamental process of life. Metabolic flux and balance are requisites to sustain life, and disruptions to this delicate balance are a major contributor to disease and aging. This is the reason we named our symposium “Metabolism and Life” since, in some sense, metabolism is life. Essentially every physiological state or disease is related to metabolism. The Sabri Ülker Symposium on Metabolism and Life was constructed on this framework and brought together a
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spectacular array of global experts and rising stars, exploring various aspects of metabolism, and young aspiring scientists. We hope that these events will lead to new perspectives, stimulate new collaborations, and inspire future scholarly efforts. I am most grateful to the speakers who kindly accepted to participate in this scientific and cultural celebration. While the past two years represented some of the greatest scientific advances and their critical importance in our lives, this period also witnessed incredible challenges in disseminating valid scientific information and defending science. As our keynote speaker, Roger Kornberg stated “Your efforts to support and encourage young scientists are enormously important, not only for science but of course, in this day of misinformation and rejection of science, for society as well. The battle for truth and science will never be won and must be fought in every generation. Despite the decline in recent years, we will gain again.”
“We are reminded that with each new discovery and the new power it brings comes new responsibility; that the fragility and sheer specialness of life require us to move past our differences and to address our common problems, to endure and continue humanity’s strivings for a better world.” Gökhan S. Hotamışlıgil, MD, PhD
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NEXT GENERATION OF SCIENTISTS
ISABEL
GRAUPERA Visiting Scientist Liver Unit of Hospital Sant Pau Barcelona, Spain
Q. How
did you decide to pursue a career in research?
Q. What
As a medical doctor, the first time you are in front of a patient you realize there are a lot of things you don’t know, and patients challenge you with different problems all the time. It was my recognition of this lack of knowledge that pushed me to engage in research as a way to answer some of the questions raised daily in my clinical practice. During my specialization training I had the opportunity to join the research group in my hospital studying the complications of cirrhosis – then I fell in love with research. I started in a clinical research group and then moved to translational/basic research. Research is a difficult path. Frequently, we don’t have positive results and all the work from weeks/months seem useless, but it’s fun as well, and the scientific discussions are really interesting and lead to new questions every time. Furthermore, when the results of a research project lead to a change in patient treatment practices, this opportunity to improve patient care is priceless. I would say that it ultimately is the potential benefits for our patients that made me pursue a career in research.
I’m a hepatologist focused on the study of non-alcoholic fatty liver disease (NAFLD), one of the most prevalent liver diseases worldwide with a prevalence rising parallel to the epidemics of obesity and diabetes. The complex pathophysiology of NAFLD is not completely known but several studies point towards an important role of adipose tissue in the development and progression of NAFLD. That is why I first became attracted to the Hotamışlıgil lab, because this lab was the first to describe the inflammatory role of adipose tissue in metabolic diseases and to describe the meta-inflammation concept. The role of the liver in metabolic disturbances in obesity is gaining interest nowadays, and therefore joining the Center and the Hotamışlıgil lab offered me an amazing opportunity to learn about metabolism and inflammation and apply this knowledge to NAFLD.
Q. Have
you encountered particular hurdles, challenges, or barriers along the way?
A research career offers endless challenges and the best conditions for success are a good mentor, a generous team to work with hand-in-hand, and sufficient funding. I have been very fortunate to have two of the best mentors and an amazing team with which to work. The challenge commenced for me when I started my own research group and tried to get funding for our research. As an MD, PhD, it has also been challenging to combine my clinical practice with lab research. With that being said, it has also been an extraordinary privilege to be able to work directly with patients and apply first-hand clinical experience to research practices.
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attracted you to join the Hotamışlıgil lab at the Sabri Ülker Center?
Q. What
particular scientific questions motivate you?
Although obesity and NAFLD are intimately linked, not all patients with obesity present NAFLD and not all NAFLD patients progress to advanced chronic liver disease and cirrhosis. Furthermore, the progression of NAFLD to cirrhosis is done at different velocities according to individual susceptibilities and also to different metabolic environments. These are the main questions presented by patients in clinical practice. In this context, because obesity is associated with the presence of a low-sterile inflammatory state, I’m most interested in understanding the role of innate immune cells in NAFLD development and progression. Are adipose tissue macrophages driving NAFLD progression through adipose-tissue-liver signaling? Are liver macrophages, under a deleterious metabolic environment, driving disease progression? Can we change the phenotype of macrophages to a more anti-inflammatory or pro-resolutive phenotype to halt NAFLD progression?
SHIJUN
DENG Postdoctoral Fellow
Q. How
did you decide to pursue a career in research?
Q. What
Actually, I had never thought that I would be a scientist when I was a child. However, when I came to choose a major after high school, I somehow found myself naturally pulled into the biological sciences. My initial exposure to scientific research was as a graduate student in the lab of Professor Christopher Elliot at the Queen’s University Belfast in Northern Ireland, UK. As is often the case, my interest to be a scientist grew as my original project rapidly evolved into exciting directions. But I was not sure I wanted to pursue a career in research until I graduated with a PhD degree from the University of Alberta in Canada.
I had heard of Dr. Hotamışlıgil as one of the world’s leading experts in metabolism and inflammation. My first encounter with his lab was a paper published in the journal, Cell, entitled ‘Nrf1 is an ER Membrane Sensor that is central to Cholesterol Homeostasis’. I was very impressed by the scientific rigor of this research done in the lab and the range of experimental approaches and the elegance of how molecular mechanisms were linked to physiology. As a scientist passionate about the study of cholesterol, I reached out to the authors and Dr. Hotamışlıgil, who patiently answered all of my questions in detail. Then I started to email former lab members to inquire about their experiences. All of them highly recommended the Center and Hotamışlıgil lab as an excellent place to perform cutting-edge research on metabolism. Then it became an easy decision for me to join the group.
Q. Have
you encountered particular hurdles, challenges, or barriers along the way?
I started to study abroad in 2011. This is my tenth year away from home and family. Last year’s pandemic made it even more difficult for me to return home. I guess my parents will have to wait longer. But, I am very grateful for their support of my career. Speaking of research, I believe that pursuing a career as a scientist is full of challenges simply by virtue of the unpredictable nature of working with experiments. Most of the time, I found my hypothesis was wrong and I had to accept it and move on to do the next series of experiments. I have gotten used to it. Our lab always emphasized how important it is to learn how to enjoy these mistakes, as they take us to new paths of discovery.
attracted you to join the Hotamışlıgil lab at the Sabri Ülker Center?
Q. What
particular scientific questions motivate you?
Atherosclerosis and associated cardiovascular disease are a major global heath burden, accounting for over 30% of global mortalities. My goal is to understand how cholesterol metabolism and inflammation interact in atherosclerosis, and how the understanding of these interactions can be useful in designing therapeutic strategies. Specifically, my research focus is investigating the role of macrophage Nrf1 in atherosclerosis. Understanding the function and mechanism of macrophage Nrf1 will provide important insights into a novel mechanism of immune-metabolic regulation in atherosclerosis and reveal a potential therapeutic target for the treatment of atherosclerosis.
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OUR COLLABORATION WITH:
REFIK ANADOL Molecular Architecture is a manifestation of infinitely dynamic and molecularly defined biological forms on the nanoscopic scale at a never before achieved detail. Based on the data collected from Professor Gökhan S. Hotamışlıgil’s years-long study at Harvard University and Sabri Ülker Center on the relationship between metabolic health and certain chronic diseases such as obesity and diabetes, the augmented sculptures of Molecular Architecture emerge from the application of cutting-edge FIB-SEM imaging, segmentation of 22,035 sections collected from a 1m µ3 volume, machine learning, and 3D constructions and printing techniques. They aim to accurately represent the spectacular resolution of the inner architecture of liver cells and their biochemical and physiological constellations of healthy and unhealthy cell structures that will define the future of global human health.
SCAN HERE
View exhibition here.
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A CONVERSATION BETWEEN GÖKHAN HOTAMIŞLIGIL AND REFIK ANADOL HOW MOLECULAR BIOLOGY, ART AND TECHNOLOGY CAME TOGETHER USING BIG DATA. Q. What
is my view of the interface between science and art? ÖKHAN: At the start of our journey, I have made the G following observations. Are art and science not processes of searching for beauty and truth? Could there be science without art, or art without science? From Architect Sinan to Leonardo da Vinci, seekers of truth and beauty have been able to see the most important universal reflections at this intersection. Scientists query everything in their quest for facts yet to be discovered or observed, while artists question everything in the pursuit of beauty, which no one has seen before. With the exciting possibility and joy of seeing something new – a brand-new thing every day – they each turn a long life full of hard labor into pleasure. Both the artist and the scientist follow “a long, narrow road.” For both, what gives them the highest inspiration and satisfaction, and “the reason for staying” on this road (Quoted from Aşık Veysel), is the creativity in their work, and the hope of being able to touch another person’s life.
REFIK: At Refik Anadol Studio & Media Lab, our multidisciplinary approach to the future of humanity confronts the complex question of redefining environments and architectural spaces through AI-based digital aesthetics at the intersection of art, technology, and science. In collaboration with scientists and academics from around the world, we aim to address timely and timeless inquiries about how the human brain, and its artificial counterpart, construct realities that encourage us to redefine spaces with a new vocabulary of world-making. Our research and artwork lay at the center of both computational and representational concerns about the perception of environments contributing to this vocabulary. Our research program builds a perfect bridge between academic research and public art, as it seeks to find ways of creating awareness regarding recent scientific and technological developments. Q. What
intrigued me about a collaboration?
GÖKHAN: What intrigued me most about Refik and his team was their endless curiosity, genuine excitement about science, and kind generosity in their time and effort to enable our dreams. It’s only because of these qualities that we were able to achieve what we have so far. In the end, our interactions with Refik allowed us to both enjoy an invaluable treasure—the possibility of seeing something that no one else has seen before and sharing it with the rest of the world in the most beautiful manner. REFIK: I was intrigued by how open-minded and enthusiastic Dr. Hotamışlıgil and his colleagues were during our discussions of the aesthetic, visual, and philosophical qualities of our collaboration. It was
amazing to witness multilayered conversations unfolding around the phrase “sense of space,” while knowing we each defined and envisioned it in a different light and scale. Dr. Hotamışlıgil and his team gave us the opportunity to challenge our virtual and immersive conception of environment(s), and redirect our attention to the productive and aesthetic conflation of nano and architectural spaces. Q. What
can the public learn by experiencing our collaborations? ÖKHAN: This collaboration illustrated the power of G the interface between science and art. On our end, this effort involved many years of work involving the acquisition of large volumes of subcellular structural data from tissue samples at different states that challenge liver function. Scientists at the Sabri Ülker Center, led by Drs. Güneş Parlakgül and Ana Paula Arruda, in collaboration with Dr. Harald Hess and C. Shan Xu at the Janelia Campus of the Howard Hughes Medical Institute, implemented advanced microscopy technologies to tissue samples and generated massive amounts of molecular architectural data.
To build the most detailed 3D architectural constructions and illustrations of this data, we initiated an extremely exciting collaboration with Refik Anadol and his colleagues. His unique expertise, creative genius, and visual magic allowed us to not only build the actual subcellular molecular architecture in spectacular detail, but also provided a 3D molecular tour inside the actual subcellular architectural structures, revealing an unprecedented level of detailed information. This perspective of biological and molecular architecture and its functional reflections may not only help us discover new metaphors for adaptability in innovative design, but also approach inherent or acquired structural failures which threaten health and survival. REFIK: Understanding architecture as a living organism in the age of big data along with advanced analytical and computational methods demands a more nuanced look into the complex relationships between the human body and the changing meaning of structure. Living things seem to possess and control tremendously rich and dynamic architectural repertoires compared to rigid architectural forms, making them more susceptible to endless permutations, randomness, disorientation, and entropy to support their ever-changing functional demands. Our exhibit on the “resolution of biological structure” explored the main theme of the 2021 Venice Architecture Biennale, “How will we live together?”, through an interdisciplinary investigation of how human vitality and unobscured anatomical spaces can help us find new metaphors for adaptability in innovative design. 27
LOOKING FORWARD
Our laboratory has completed the first year of our second quarter-century of research. What lies ahead is anyone’s guess, but I am very optimistic that science and our efforts to advance will remain on an increasingly positive trajectory. There is a multitude of reasons for this, but there are two that particularly stand out—first, the people, and second, the resources required to support the basic research enterprise that the Center and our Institution offers. Over the past twenty-six years at Harvard, I have been blessed to work with hundreds of fellows, students, visiting scientists, research assistants, research scientists, research associates, technicians, and support staff. Many have come here as newly minted PhDs, others at the conclusion of their bachelor’s program, seeking to enter the field of scientific research in an effort to understand if this is their true passion. Still, others have come to work with us having experienced multiple successes, looking to contribute to a dynamic team while taking their skills to the next level. Serving as a mentor for all, I endeavor to recognize and celebrate their individuality. It is the various gifts that each individual has brought to the fore, in a collaborative and supportive effort, to focus on bringing the most creative and original thoughts to the crucible that is our laboratory.
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Representing a multitude of diverse ethnicities, religions, cultural and educational experiences, fascinating personal stories, and traits, these individuals have been able to come together to make essential discoveries. Together we continue to untangle the mysteries of metabolism in our journey to answer some of the most vexing questions that have prevented humans from solving the greatest public health threats—chronic diseases. The team that is the Sabri Ülker Center is, therefore, able to bring together our combined intellectual and creative dynamism with our invaluable collaborators throughout the world, in seeking the answers to these questions—questions we must seek answers for, in order to generate translational impact and to improve the quality of human life for all.
Nutrient, Genetic, and Metabolic Research
Nutrient, Genetic, and Metabolic Research
Harvard T.H. Chan School of Public Health 665 Huntington Avenue Building 1 Room 605 Boston, Massachusetts 02115
Visit us: www.gsh.sph.harvard.edu NUTRIENT, GENETIC, and METABOLIC RESEARCH Follow us: @sabriulkerctr