Harvard Sabri Ülker Center Achieves a World First

Harvard Sabri Ülker Center Achieves World First Research conducted by Prof. Dr. Gökhan Hotamışlıgil, Director of the Harvard Sabri Ülker Metabolic Research Center, and his team using "Focused Ion Beam Scanning Advanced Electron Microscopy" has been completed. In a study conducted for the first time at this scale and resolution worldwide, three-dimensional molecular architecture of intact liver tissue was imaged, revealing dynamic structural differences within cells in both health and disease states. The most important finding of the research is that molecular repair of the damaged form can restore normal metabolic functions within the cell. The Harvard Sabri Ülker Metabolic Research Center has achieved a world first. Prof. Dr. Gökhan Hotamışlıgil and his team imaged the three-dimensional molecular architecture of intact liver tissue using "Focused Ion Beam Scanning Advanced Electron Microscopy." Through high-resolution 3D imaging of the liver, the metabolic effects of structural differences within cells in both health and disease states can now be monitored.

Revealed After Years of Research

It is known that organs and tissues in our body must adapt to the challenges they face in meeting functional demands, maintaining homeostasis and sustaining life, and have developed different adaptation mechanisms to this end. Following years of research, Harvard Sabri Ülker Center researchers Güneş Parlakgül and Ana Arruda demonstrated that molecular architectural arrangements play a striking role as an important new mechanism for adaptation and have a critical function in maintaining metabolic balance. Since microscopy became available, it has been known that cells with completely different functions in the body display vastly different molecular internal architecture. However, examining these structures, particularly their natural details within the organ where they are located and any possible changes they undergo, presents significant technical challenges. Commenting on the subject, Prof. Dr. Gökhan Hotamışlıgil stated: "In this study, Güneş and Ana succeeded both in revealing these structures in extraordinary detail at the highest resolution ever obtained at tissue level and in correlating them with liver cell function. A study of this scale was naturally only possible through important collaborations with experts from many disciplines, most importantly Dr. Shan Xu and Dr. Harold Hess from the Howard Hughes Medical Institute."  

Focused Ion Beam Scanning Advanced Electron Microscopy Used

Classical architectural approaches generally define the relationship between form and function as static and stationary. This view is also widespread in the biomedical field. However, in this study, center researchers demonstrated that intracellular molecular architecture in a biological system is both extremely "complex yet highly ordered" and equally "mobile or dynamic." In this study, the team conducted a very thorough investigation using advanced imaging platforms such as focused ion beam scanning advanced electron microscopy (advanced FIB-SEM), artificial intelligence, machine learning, deep learning, neural networks and many other analytical tools, alongside molecular, biochemical and physiological approaches.

Comparative Studies Conducted

As a result, the molecular architectural internal design of hepatocytes within liver tissue, as they are located, is revealed across a large tissue volume, in numerous cells and at extraordinary resolution (8 nm voxels, or three-dimensional pixels, in the x, y and z planes). Additionally, comparative studies conducted both during fasting and feeding cycles and between lean and fatty liver tissues reveal severe structural changes and transformations observed during feeding and obesity. Comparative analysis of intracellular structures in liver tissues of lean and obese animals reveals marked changes, irregularities and damage in endoplasmic reticulum (ER) organelles, which perform a kind of packaging and transport function in these cells, and in relation to mitochondria. This provides researchers the opportunity to study the relationship between molecular architecture and metabolic activity, namely the relationship between molecular form and function. The very interesting functional results of the study are the repair of these structural changes in obesity and the restoration of intracellular molecular organization, which reveals striking changes in metabolism. To achieve this, the team develops dozens of different molecular and genetic strategies and succeeds in repairing the damaged molecular architecture in obesity using many genetically modified mouse models. This structural repair can restore metabolic disorders in the liver to normal within approximately two weeks; problems such as fatty liver, insulin resistance and excessive glucose production are corrected by merely intervening in the architectural structure. Thus, a new control mechanism that regulates metabolism and adaptation and an important problem leading to disease are revealed. Hotamışlıgil, who sees this study as one of the most important milestones achieved at the Harvard Sabri Ülker Center, continued his remarks as follows: "An important part of our vision at the center is seeking answers to difficult questions through sustained and in-depth research. This study is a very exciting example of that. The window opened by this type of fundamental research presents us with many new questions. Of course we will follow up on these and conduct investigations into long-term implementation opportunities. I congratulate Ana and Güneş, the architects of this 'architectural' study, and thank all the scientists with whom we have had the opportunity to collaborate and all members of our center for their contributions." Prof. Dr. Gökhan Hotamışlıgil will meet with Turkish academics in Istanbul at the end of March to present research conducted at the Harvard Sabri Ülker Center and discuss developments in the scientific world.