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Autophagy Community Daniel J. Klionsky

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Life Sciences Institute, University of Michigan, 210 Washtenaw Ave., Ann Arbor MI, 48109-2216, United States Accepted author version posted online: 03 Mar 2015.

Click for updates To cite this article: Daniel J. Klionsky (2015): Autophagy Community, Autophagy To link to this article: http://dx.doi.org/10.1080/15548627.2015.1017225

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Walter Balduini Email: [email protected] Research focus Mechanisms of neurodegeneration after brain ischemia and potential

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neuroprotective treatments

Model system In vivo models of perinatal hypoxia-ischemia

Education and career 1981, PhD pharmacy degree, University of Urbino “Carlo Bo”, Urbino, Italy. 1981–1982, postdoctoral Fellow, Institute of Pharmacology and Pharmacognosy, University of Urbino. 1983, postdoctoral fellow, Institute of Pharmacological Sciences, University of Milan, Italy. 1986–1987, 1988, 1989, 1993, visiting senior fellow, Department of Environmental Health, University of Washington, Seattle, WA, USA. 1988, assistant professor, Faculty of Pharmacy, University of Urbino. 2001–present, associate professor, Faculty of Pharmacy, University of Urbino.

Why do you study autophagy? The main aim of my research is to assess new pharmacological treatments for perinatal hypoxiaischemia-induced encephalopathy. Our group began studying the role of autophagy in neurodegeneration when it was considered mainly a mechanism of cell death. Studying the activation of autophagy in a model of perinatal hypoxia ischemia we found that, in contrast to the then prevailing view, autophagy was activated for survival and was strictly connected to apoptosis and necrosis. We also showed that activation of autophagy is parallel to that of survival signaling and we recently found 1

a close connection with the unfolded protein response after endoplasmic reticulum stress indicating that autophagy is at the intersection of several key signaling pathways. Whether a cell survives or dies depends on the delicate equilibrium among these pathways. Of course, studying autophagy in a model of perinatal hypoxia-ischemia in vivo does not allow detailed analysis of the molecular mechanisms involved in formation of autophagosomes, but can give a picture of the role that autophagy-associated

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proteins may have in the neurodegenerative process.

What do you think is a key question in the autophagy field? Can autophagy be a target for potential neuroprotective treatments? It is difficult to say. The only certainty we have now is that autophagy over-activation is critical for the neuroprotective effect of ischemic or pharmacological preconditioning. In my opinion an important question to address in the near future is how cells target selective parts of the cytoplasm to be included into autophagosomes as a function of the cell need. Reticulophagy or ribophagy, for example, could be a fast way to block protein synthesis during endoplasmic reticulum stress which may save energy to be used for other cell needs, lengthening survival. Revealing these mechanisms may help to identify new pharmacological targets for neuroprotection.

Is teaching a substantial part of your current position? I spend a significant amount of time teaching, about 80-90 hours/year. Actually, I teach toxicology to pharmacy students but I previously taught applied pharmacology and molecular pharmacology. Teaching a subject such as toxicology helps to put together the large amount of information emerging from basic research, but also helps to keep in mind that cell death occurs in a context of not only a single cell, but of an organ and the whole body.

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Personal comments I live in a nice house in the country with my family, 2 dogs and 2 cats. My wife is a high school teacher and my 2 sons are university students. The house keeps me quite busy when I am not at work, but when I have time I like to travel and meet new cultures. I also like to ride my motorcycle around Europe. I enjoy sports activities, movies and books, especially novels. With regard to the latter, I like the classic

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and contemporary Italian and European writers, but also writers from Latin America (e.g., Gabriel Garcìa Màrquez and Isabelle Allende), the USA (e.g., Kaled Hosseini) and Japan (e.g. Yasunari Kawabata and Haruki Murakami).

Paolo Bonaldo

Email: [email protected]

Research focus Role of the extracellular matrix in tissue homeostasis and diseases

Model system Primary mammalian cell cultures, mouse models, zebrafish

Education and career 1986, degree in biology cum laude, University of Padova, Italy. 1986–1989, postgraduate fellow, National Cancer Institute CRO-IRCCS, Aviano, Italy. 1990, PhD, Medical School, University of Padova; advisor: Alfonso Colombatti. 1993–1995, visiting scientist, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany; advisor: Peter Gruss. 1995–1998, assistant professor, Medical School, University of Padova. 1998–2004, associate professor, Department of Histology, University of Padova, Italy. 2005–present, professor of cell biology, Department of Molecular 3

Medicine, University of Padova.

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Why do you study autophagy? During the past 2 decades, the main focus of my research was the study of the extracellular matrix and in particular the role of its components during development and disease. We produced mouse models for different extracellular matrix components, including COL6/collagen VI, a main matrix molecule involved in different myopathies and muscular dystrophies. Our recent work provided the first evidence that a failure of the autophagic machinery is involved in the pathogenesis of muscular dystrophies, opening the way to clinical trials in patients. I entered the field of autophagy by chance, when investigating the mechanisms causing accumulation of dysfunctional organelles in muscle fibers of mice and patients affected by muscular dystrophy. We pioneered the finding that an inefficient regulation of autophagy contributes to muscle wasting and weakness in these diseases, and showed that restoration of a proper autophagic flux is beneficial and counteracts muscle pathology. My lab is now expanding its interest in the regulation of autophagy in skeletal muscle under physiological and pathological conditions.

What do you think is a key question in the autophagy field? Although it has become increasingly clear that autophagy plays a fundamental role in cell homeostasis, we can expect that this process is much more complex as well as differently regulated under a number of cell conditions and based on specific tissue requirements. A key question is how those different processes that today we collectively consider as ‘autophagy’ are regulated and executed, as well as their interplay with other key processes of the eukaryotic cell, such as trafficking, endocytosis and exocytosis. Another fascinating aspect is the relationship between autophagy and some fundamental cell events like proliferation, commitment and differentiation.

Why is the field of autophagy important to you? Besides its obvious significance in a number of physiological processes, I think that autophagy represents a highly attractive therapeutic target for counteracting a number of human disorders.

If you could meet any scientist, currently living or from the past, who would it be and why? Charles Darwin, whose revolutionary theories about evolution and natural selection still pervade not only science but also our entire society after more than a century.

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What one scientific discovery do you wish you had made? Deciphering the genetic code, together with Khorana, Nirenberg and the other brilliant teams of the time. More than a discovery, a very exciting and ambitious ‘fishing expedition’ for the most important language that encompasses the entire life on earth.

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Is teaching a substantial part of your current position? As a faculty member at an academic institution, teaching is a very substantial part of my daily working activity. I teach primarily cell biology and functional genomics at both undergraduate and graduate levels in the medical, dentist, and biotechnology courses. I am also coordinator of the PhD program on molecular and developmental biology of the University of Padova. Although teaching diverts a large amount of time and effort from my research work, I hope I can drive students towards critical thinking and transmit to them my enthusiasm for science. I feel deeply gratifying that I had the chance to have some of my former class students in my lab and helped them develop into creative scientists.

Personal comments I am glad be a scientist, and if I could go back and start over I would like to become again a scientist— if not in the biology field, most likely it would be in astronomy. In my free time, my favorite hobby is listening to experimental music from the past 60 years (that’s not a commonly heard genre of music!), and watching vintage sci-fi films. Needless to say, my top favorite movies are “Forbidden Planet”, “This Island, Earth” and “The Incredible Shrinking Man”. I am a night bird, and regularly stay awake until late at night reading books and listening to music. In my free time, I enjoy staying with my wife, my kids (now in their 20s, one boy studying electronic engineering and one daughter studying economy), as well as with my dog (a lovely mongrel named Willy).

Magdalena Maria Rost-Roszkowska Email: [email protected] Research focus Programmed cell death and autophagy in animal epithelia Model system Midgut epithelia in Hexapoda, Crustacea, Myriapoda, Tardigrada and Annelida 5

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Education and career 1997, MSc in Biology, Department of Animal Histology and Embryology, Faculty of Biology and Environmental Protection, University of Silesia. 1998–2002, PhD, University of Silesia; advisor: Professor J Klag. 1999, MSc in, Chemistry, Faculty of Mathematics, Physics and Chemistry, University of Silesia, Poland. 2002–present, assistant professor, Department of Animal Histology and Embryology, University of Silesia, Poland; 2008–present, professor, Silesian Medical College, Katowice, Poland. 2011, Habilitation, Faculty of Biology and Environmental Protection, University of Silesia, Poland. Why do you study autophagy? The main aim of my team’s study is to analyze the ultrastructure of the digestive epithelia in invertebrates, which can be exposed to different factors of the external environment. Because of the fact that the midgut epithelium is treated as one of the barriers in the organism against stress factors, we pay attention to all processes of cell death that occur in this epithelium. One of the mechanisms is autophagy. Therefore, we are trying to explain what is the role of this process in functioning of the midgut epithelium and if there is a relationship between autophagy and apoptosis. We have been studying the activation of autophagy according to the appearance of pathogens or toxic substances (e.g., heavy metals) with special emphasis on species that are treated as bioindicators of the environment. Some months ago, we started our studies on the role of autophagy during animal oogenesis, mainly in the cytoplasm of the nurse cells and oocytes. Additionally, we would like to answer the question of whether autophagy in animal epithelia depends on a day/night cycle in nocturnal and diurnal invertebrates. What do you think is a key question in the autophagy field? I think that the main and essential problem is the relationship between autophagy and programmed cell death in a proper functioning of tissues and organs. Why is the field of autophagy important to you? As we know we all live in a polluted environment and many xenobiotics can affect us and other organisms. I think that studying processes such as autophagy will help us to understand how organisms can protect themselves against stress factors. In addition, I would like to analyze the relationship between the proliferation and differentiation of regenerative cells (midgut stem cells) and processes such as autophagy or apoptosis. If you could start over and choose a different career, what would it be? I would choose scientific research one more time. Due to working in a laboratory, discovering and analyzing animal tissues, I feel that each day of my life differs from every other. Is teaching a substantial part of your current position? If so, what do you teach. Does it benefit your research, or benefit from your research? My teaching activities include lectures and laboratories for students and I am responsible for introducing to them the knowledge on animal embryology, endocrinology and histochemical and immunohistochemical methods. I also supervise some MSc and PhD students working on their thesis in the laboratory. Personal comments 6

Some years ago, I used to spend a lot of time with my husband on visiting historical reconstructions, military events, skiing and yachting. However, now I am the mother of 1.5-year old Max and have not so much time to do that. Therefore, I try to take him with me wherever I go and teach him, for example how the bees or the mosquitos fly. I also need to have some time for my two beautiful Persian cats.

Ilse Vanhorebeek

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Email: [email protected]

Research focus Mitochondria and autophagy in critical illness

Model system Human liver and muscle biopsies, myoblasts and peripheral blood mononuclear cells; tissues from rabbit and mouse models

Education and career 1997, engineer, Applied Biological Sciences, KU Leuven, Leuven, Belgium; 2002, PhD, Pharmaceutical Sciences, KU Leuven; advisor: Prof. Peter Declercq and Prof. Myriam Baes. 2003– 2009, postdoc, Laboratory of Intensive Care Medicine, KU Leuven; advisor: Prof. Greet Van den Berghe. 2009–present, research professor, Laboratory of Intensive Care Medicine, KU Leuven.

Why do you study autophagy? My first contribution to the research field of intensive care medicine was the identification of stress hyperglycemia-induced mitochondrial damage as a key player in multiple organ failure and the high risk of death characteristic of critical illness. Studying mitochondrial repair mechanisms, my mitochondrial research track continued into the area of autophagy. Importantly, we observed a phenotype of insufficient autophagy activation in organs from artificially fed prolonged critically ill patients. This phenotype appeared important in determining adverse outcome, with more severely suppressed autophagy in nonsurviving versus surviving critically ill animals.

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We identified early continuous artificial nutrition as a major culprit in the suppressed activation of autophagy, with adverse effects on vital organ function in critically ill animals and patients. The clinical research team demonstrated reduced morbidity and accelerated recovery when tolerating a severe caloric deficit up to one week of critical illness, as compared with early administration of parenteral nutrition (i.e., intravenous feeding) to reach the caloric target. In view of the crucial role of autophagy in damage removal, and fasting being the most potent physiological activator of autophagy, suppressed autophagy with early continuous parenteral feeding may have played a role. In muscle biopsies from these patients, we indeed demonstrated suppressed activation of autophagy by early parenteral nutrition, which correlated with a higher incidence of clinically relevant muscle weakness. Remarkably, muscle atrophy markers were not related to muscle weakness. Nevertheless, a severe caloric deficit can only be tolerated for a limited time.

Why is the field of autophagy important to you? Our findings of suppressed autophagy activation, at least partly due to artificial feeding of critically ill patients, open perspectives for pharmacological reactivation of autophagy to improve patient outcome. A pilot study on rapamycin administration to critically ill animals supported this concept, although, further research is needed to find a safe and efficient alternative for the immunosuppressive rapamycin for clinical use.

What do you think is a key question in the autophagy field? Staying in my own research field, I consider it crucial to study the impact of pharmacological autophagy activation during critical illness in an adequately powered randomized clinical study.

What do you hope to achieve in your scientific career? Being part of a well-functioning team of basic and clinical scientists, I hope to substantially contribute in making a difference in the care for critically ill patients, with the ultimate goal of improving the acute and long-term outcome of these very vulnerable patients.

Which paper in your research field represents seminal work on autophagy? Initial studies on autophagy in critical illness were performed in models of acute sepsis or trauma, implicating a fasted state. The reported autophagy activation was interpreted as a detrimental response contributing to hypercatabolism and muscle wasting. We challenged this concept in our 2013 Lancet Respiratory Medicine paper, showing clinical outcome benefit with autophagy activation. This randomized study showed that relative starvation of patients early during critical illness did not affect 8

muscle wasting, but allowed more efficient activation of autophagy and reduced weakness as compared with supplemental parenteral nutrition.

Is teaching a substantial part of your current position?

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My current academic position is focused on research with, apart from supervising students in the lab, only a limited teaching assignment. In my main course I teach medical students how to define and address scientific problems, starting from the topic of choice “Endocrine and metabolic disturbances during critical illness”, in which I integrate part of my research.

Personal comments My free time is largely reserved for visiting family and friends. I very much like hiking and really enjoy being outdoors surrounded by beautiful nature. Although Belgium has many beautiful places, I also like to travel abroad, being attracted by mountains, lakes, forests, wildlife…and I like reading books (during holidays).

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