Interview Dr. Sergio Lavandero: "The way of the Chilean science for understanding Autophagy"

Interview Dr. Sergio Lavandero: "The way of the Chilean science for understanding Autophagy"

The concept of Autophagy has been taking a substantive relevance in recent years, even during this 2016, when the Nobel Prize in medicine, went to the Japanese scientist Yoshinori Ohsumi (Fukuoka, 1945), awarded for his contributions to the molecular mechanisms that regulate this process.

Hundreds of scientists around the world were pleasantly surprised by the news of the Nobel Prize in medicine 2016, which generated a great interest for this physiological mechanism. Producing an impact in the scientific community, which more and more It includes researchers who are committed to study the Autophagy.

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In our country – and since the year 2002 – Dr. Sergio Lavandero, Director of the Advanced Center for Chronic Diseases (ACCDiS) - Centre of excellence national formed by the University of Chile and the Pontifical University Catholic of Chile with the support of program FONDAP of CONICYT, and that it aims to identify commonalities of cardiovascular disease and cancer, to offer alternatives for prevention or control of damage caused by them in our population - has done enough research on Autophagy, by which this milestone marks the beginning of a new and promising era of research. Since, in the words of different media, and the scientific community, "Ohsumi discoveries led to a new paradigm in our understanding of how the cell recycles its content".

laundry room-2Dr. Sergio Lavandero is a prominent Chilean scientist, renowned for its high quality research and effective productivity. Which boils down, in 218 publications to his credit, being cited more than 11.027 times according to Google Scholar, which is considered important in any field of science. He has 42 publications in the area of Autophagy, the central topic of this chronicle.

Currently is Professor Titular of the Faculty of Sciences chemical and pharmaceutical, and of the Faculty of medicine, University of Chile. He is also adjunct professor in the Division of Cardiology, University of Texas Southwestern Medical Center (Dallas, Texas). During his career, Dr. Lavandero was Chairman and member of the upper Council of science of Fondecyt, President of the Chilean society of Biochemistry and Molecular Biology and member of the Council for evaluation and Vice-Rector of research of the University of Chile. Prof. Lavandero is also member of the Chilean Academy of Sciences.

It integrates the editorial boards of the magazines Circulation, American Journal of Physiology Endocrinology & Metabolism, Cell Death & Diseases and BBA Molecular Basis of Diseases, has also been revising ad hoc prestigious international magazines and national and international agencies that support scientific research.

Then the interview that the biology society of Chile, was Dr. Sergio Lavandero.

What is it meant by Autophagy?

Autophagy is a mechanism of cell degradation that allows the removal of proteins and organelles both normal and altered. The name Autophagy (etymologically means "eating itself") and was coined by the prize Nobel Dr. Christian de Duve (1974).

Basal Autophagy is a homeostatic mechanism for cleaning and recycling that operates inside all our cells. However, it can be activated or inhibit above this baseline level in response to various stress conditions. Autophagy is a planned, sequential and dynamic process characterized by the presence of vacuoles in double membranes in the cell cytoplasm.

How has the history of Autophagy developed?

It began in 1955 with the discovery of Lysosomes by Dr. Christian de Duve, and his subsequent description of "autophagic vacuoles" in 1963. Then, established that fasting induces Autophagy in the liver and that both the deprivation of amino acids and glucagon, are responsible for the aforementioned effect primary signals. After this stage, initially descriptive and morphological, spent even a long period of silence, until in 1980, he began to understand the molecular mechanisms of how they form and end the autophagic vacuoles.

He was established that Autophagy is a very dynamic process that can be subdivided into four stages: initiation, elongation, closure and merger, and finally, degradation. At the same time, a measure which the vacuole is formed (autofagosoma), is capturing the material to degrade. The process continues to formation of the autofagolisoma (or also known as autolisosoma) fusion of the autofagosoma with a lysosome, compartment running the degradation due to the action of Lysosomal enzymes and acid pH (see Figure 1).

The silent work of Dr. Otsumi, studying the autophagic yeast process, was key to identify and characterize proteins ATG involved and regulate the four key stages. Mutants of yeast, Dr. Otsumi found the basic genes that code for these regulatory proteins of the autophagic process. Dr. Otsumi also had another merit, through these works in Autophagy, formed generations of young outstanding Japanese scientists who have continued their legacy.

How have these investigations contributed to a greater knowledge and potential applications?

The team of Japanese scientists, led by Dr. Ohsumi created a transgenic mouse "Autophagy sensor" that expresses a protein formed by the protein Atg8 (or LC3) artificial recombinant coupled with green fluorescent protein (GFP) in all of their cells. The fast up to 48 h of these animals increased the increase in number of vacuoles autophagic LC3-GFP positive in various organs (liver, kidney, heart, diaphragm, skeletal muscle, etc.) in relation to its controls, reaching maximum in different magnitudes to 24 or 48 hours post-ayuno. Surprisingly, both the heart and some muscles were the organs that more experienced Autophagy. Then these researchers asked when do we experience the maximum physiological fast? This question was answered analyzing Autophagy before and during childbirth, as well as during the first hours post-nacimiento in various tissues of mice which over - express LC3-GFP protein.

Before birth, all requirements are provided by the mother to the fetus through the umbilical cord. However, this situation changed abruptly when the cord is cut at the time of the birth. In addition, normally the newly born not receiving breastmilk until after 24 or 48 hours after the birth. Our reserves of fat are not exactly abundant, so there was the enigma of how survived this critical stage of nutritional stress?

In that way, the Dres. Otsumi and Nizushima discovered that the heart and various skeletal muscles experience a transient and intense activation of the process Autophagy providing energy substrates to the newborn (Nature 2004; 432:1032-6).

It deregulates the Autophagy?

If by the way. Both the overactivation and absence of Autophagy is associated with the development of various pathologies such as cancer, neurodegenerative diseases, cardiovascular diseases, among others. In the case of myocardial infarction, cardiomyocytes undergo severe nutritional stress due to ischemia (lack of blood supply) generated by an atherosclerotic plaque or a thrombus. In this case, Autophagy is activated and meets a protective function, providing power to those cardiomyocytes under stress. If crashes genetic or pharmacologically activation of Autophagy, cardiac function is impaired. On the other hand, hypertension is a disease that affects 30% of Chileans and to get older its prevalence increases significantly. Today, we know that Autophagy is activated in the heart of the hypertensive. In this case your activation is harmful and half of the pathological process. In this scenario, your lock genetic or pharmacological prevents the deterioration of the function contractile cardiac. Today, we know that Autophagy has a dual behaviour. Janus in Roman mythology, God of doors, beginnings and endings, a God depicted with two faces.

For more information about the role of Autophagy in the cardiovascular system I refer you to review articles: Lavandero et to the. "Cardiovascular autophagy: concepts, controversies, and perspectives". Autophagy. 2013; "9:1455-66 and Lavandero et to the." "Autophagy in cardiovascular biology". J ClinInvest. 2015; 125:55-64.

What regulates Autophagy?

Several, but by far rapamicinaes is the best known. This drug immunosuppressive generated as a product of the bacterium Streptomyceshygroscopicusdiscovered in 1965 in a sample of soil of Easter Island ("Rapa Nui"), an activator of Autophagy by inhibiting a component of the complex mTORC1. This complex has specific protein kinase activity, so its action is explained by the phosphorylation of specific proteins ATG and its corresponding inhibition. Both the deprivation of amino acids, and rapamycin share mechanism of action in relation to Autophagy. On the other hand, chloroquine, anti-malaria medication, is an inhibitor of Autophagy by blocking the final stage of the process. However, there is a long list of other known chemical compounds and others under development that positively or negatively regulate the autophagic process.

Does research ACCDiS in Autophagy?

ACCDiS investigates two chronic diseases: cancer and cardiovascular diseases. Both are diseases of greatest relevance in Chile by their morbidity and mortality. In fact they realize almost 60% of total mortality in Chile. Inside the Centre, there is a large group of scientists working on the theme of Autophagy and its link with the genesis and development of the above mentioned diseases. One of these researchers, is Dr. Alfredo Criollo, researcher associate of ACCDiS and academic in the Faculty of Dentistry of the University of Chile.

Dr. Criollo has 36 publications on this subject, in high-impact journals. It was formed in this area next to the Dres. Guido Kroemer (France) and Joseph Hill (USA). Dr. Criollo is organizing the Workshop ICGEB "Autophagy: Physiological and Pathological Roles" to be held between 23-24 November, 2016 at the Aula Magna of the Faculty of chemical & pharmaceutical sciences, University of Chile.

On the other hand, there is an obvious interest of the subject of Autophagy in Chile, reflected in the number of researchers with original research lines in Autophagy in Santiago and throughout our country.

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Figure 1. Time course of Autophagy in cells (U2OS) bone cancer. The photographs correspond to U2OS cells transfected with the plasmid RFP-GFP-LC3 and exposed to nutritional stress to evaluate flow autophagic. Panels A and B show the presence of yellow and red, vacuoles which correspond to autofagosomas and autolysosomes, respectively. Photographs of the laboratory of the Dr. Alfredo Creole.

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