Autophagy
ISSN: 1554-8627 (Print) 1554-8635 (Online) Journal homepage: http://www.tandfonline.com/loi/kaup20
Autophagy researchers To cite this article: (2014) Autophagy researchers, Autophagy, 10:3, 393-396, DOI: 10.4161/ auto.27581 To link to this article: http://dx.doi.org/10.4161/auto.27581
Published online: 17 Jan 2014.
Submit your article to this journal
Article views: 156
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kaup20 Download by: [50.201.204.73]
Date: 06 November 2015, At: 00:01
autophagy community
cell cycle news & views
Autophagy 10:3, 393–396; March 2014; © 2014 Landes Bioscience
Autophagy researchers Patricia Boya
Research focus I want to understand why the process of autophagy is essential to maintain cellular homeostasis and determine its role in animal physiology and pathology.
Model system We use the retina as our model system, which provides us with a window into the brain, and we perform in vivo studies using autophagy-deficient mice.
Education and career 2000, PhD, cell biology, University of Navarra, Spain; advisors: María Pilar Civeira and Esther Larrea. 2001–2004, postdoctoral researcher, Centre National de la Recherche Scientifique (CNRS), Paris, France; advisor: Guido Kroemer. 2005, postdoctoral researcher, University of Cambridge, UK; advisor: Aviva Tolkovsky. 2005–2009, Ramón y Cajal Scientist, Centro de Investigaciones Biológicas-Consejo Superior de Investigaciones Científicas (CIBCSIC), Madrid, Spain. 2009–present, staff scientist, CIB-CSIC.
Why do you study autophagy? While studying the role of lysosomes in apoptosis as a postdoctoral researcher, I found that lysosomal damage and subsequent permeabilization preceded cell death. I observed that cell death was associated with autophagosome accumulation, a phenotype indicative of
autophagic cell death. However, blockade of autophagy in these cells fails to prevent cell death and even increases it. Although these results were puzzling at first, I realized after attending the first Gordon Research Conference on Autophagy in Health, Development, and Disease in 2003 that by causing lysosomal damage I was blocking the final steps of autophagy. These results demonstrated that cells require functional autophagy to survive in normal and nutrient-deprived conditions, and provided the first evidence of a cytoprotective role of autophagy in mammalian cells. Currently I am interested in understanding the physiological roles of autophagy as well as its role in disease. In my lab, we are investigating the contribution of autophagy to the development of the nervous system, using the retina as a model. We want to unravel the relationship between autophagy and basic processes such as the cell cycle, cell differentiation, and cell death, and determine how intercellular crosstalk regulates tissue homeostasis. We have demonstrated that the maintenance of ATP levels by autophagy is essential for eliminating apoptotic cells during cell death associated with retinal neurogenesis. We are currently studying retinal development in knockout mice that lack specific autophagy regulators. As autophagy is a relatively new field, many of the necessary analytical tools are still being developed. Given that we mainly work in vivo, we are currently developing automated algorithms to quantify autophagic flux by image analysis in tissue. We also wish to understand why so many pathological processes, (e.g., cancer, neurodegenerative conditions) involve autophagy dysregulation. We have demonstrated that autophagy plays a cytoprotective role following axonal damage and in animal models of Parkinson disease. Moreover, we have described crosstalk between macroautophagy and chaperone-mediated autophagy during aging in the retina. Studies in our laboratory have also demonstrated that aging attenuates macroautophagy, an effect that is partially compensated by an increase in chaperone-mediated autophagy in specific retinal cell types.
We are currently searching for new therapies for retinal diseases including glaucoma and retinitis pigmentosa, a genetic retinal dystrophy that results in photoreceptor death, leading to blindness. I am a cofounder of ProRetina Therapeutics, a spin-off seeking to utilize some of the compounds that may modulate autophagy for clinical use.
What do you think is a key question in the autophagy field, and where do you think the field is heading? Autophagy is a very complex process that requires tight coordination. The identification of new regulators of this process will shed light on cell- and tissue-specific regulation of autophagy. It will be very interesting to identify the different roles of autophagy in maintaining homeostasis in tissues, and to determine how this recycling pathway participates in so many essential tasks, from the removal of cellular debris and damaged organelles to maintaining vision and participating in the immune response. Another emerging field is the complex crosstalk between different degradative pathways, as observed during aging and in autophagy-deficient mice.
What do you hope to achieve in your scientific career? I have been always interested in disease and the importance of understanding molecular mechanisms in order to develop new treatments to improve human health. I have several ongoing collaborations with biotech companies to find new therapeutic compounds that target autophagy. I study basic processes and try to apply this knowledge to the search for new therapies. Another goal is to maintain my curiosity and to continue enjoying research as much as I do now.
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 job does not require teaching but I enjoy it, and I currently teach some undergraduate and master’s courses. In addition, I am
www.landesbioscience.com Autophagy
393
©2014 Landes Bioscience. Do not distribute.
Downloaded by [50.201.204.73] at 00:01 06 November 2015
Email: [email protected]
cell cycle news & views
to discuss new discoveries and to influence science policy. In addition to my position on the steering committee, I have been involved in the organization of the Career Programme at ESOF, a series of events specifically aimed at young scientists. I am also very interested in scientific photography, and have had many images from my research projects published on journal covers.
Personal comments We have 2 children, with whom I love spending time. We like to be outdoors, watching birds and taking photographs to try to capture the beauty of nature. I am a very social person and enjoy good company and food. Cooking and performing experiments have a lot in common, and now that I spend less time at the bench, cooking provides me with a way to relax.
Maria T Diaz-Meco Email: [email protected]
Downloaded by [50.201.204.73] at 00:01 06 November 2015
Research focus Nutrient sensing in the regulation of cell growth and metabolism
Model system In vivo knockout mouse models, and human cancer and normal cell lines
Education and career 1988, BS, chemistry, University of Madrid, Spain. 1991, PhD, biochemistry and cellular and molecular biology, University of Madrid; advisor: Jorge Moscat. 1991–1996, postdoctoral scholar, Center of Molecular Biology “Severo Ochoa” Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. 1996–2003, assistant professor, Center of Molecular Biology “Severo Ochoa” CSIC. 2003–2006, associate professor, Center of Molecular Biology “Severo Ochoa” CSIC. 2006–2010, associate professor, Department of Cancer and Cell Biology, University of Cincinnati, OH, USA. 2010–2011, professor, Department of Cancer and Cell Biology, University of Cincinnati. 2011–present, professor, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
Why do you study autophagy? My interest in autophagy stems from my work on SQSTM1/p62, a signaling hub and also a cellular metabolic switch in autophagy. Since its initial discovery by our laboratory as an interacting partner of the aPKCs/atypical protein kinase Cs, SQSTM1 has emerged as a key molecule in the control of cell growth, cancer, and metabolic homeostasis. This multifunctional role is accounted for by its ability to bind other critical intermediaries through its multidomain organization. In this regard, its interaction with TRAF6 serves to activate NFKB, further emphasizing its role in cancer
394
and inflammation. Recently, through an unbiased proteomic approach, we have found that SQSTM1 binds RPTOR/raptor, and in complex with TRAF6 is an integral part of MTORC1 in the nutrient sensing response. Interestingly, SQSTM1 is subject to constant degradation via autophagy due to its binding to LC3 through a well-defined sequence motif in SQSTM1 termed the LIR. Since MTORC1 is a negative modulator of autophagy, these findings establish SQSTM1 as a key node of control of nutrient sensing and autophagy through its interactions with MTORC1 and LC3. This is of special relevance in light of the proposed role of SQSTM1 as a receptor in selective autophagy for the delivery of polyubiquitinated proteins and damaged organelles, such as mitochondria, into the autophagy proteolytic pathway. Thus, in addition to its signaling function, SQSTM1 can also play an essential role in cellular detoxification by maintaining low levels of misfolded proteins and damaged mitochondria, thus ensuring low levels of toxic ROS and a healthy metabolism. All these functions are critical for cell survival and tumor initiation and progression, which points to SQSTM1 as an important node for cancer and metabolic homeostasis. Therefore, I think that studying SQSTM1 using relevant in vivo models we will be able to unravel the intricacies of metabolic reprogramming in cancer and other diseases, which will inevitably result in the identification of novel and more selective therapeutic targets.
What do you think is a key question in the autophagy field? Finding the molecular mechanisms that govern the interplay of autophagy and MTOR signaling, and identifying the direct sensors of nutrients that mediate these signals would be
crucial to a better understanding of cancer cell metabolic reprogramming, and to design potential therapeutic interventions in the MTOR pathway. An additional key question remains the role of autophagy in cancer and its connection with cancer metabolism. It is becoming apparent that the ability of autophagy to maintain the quality control of mitochondria in the stressed cell perhaps through SQSTM1 is central to the regulation of oxidative phosphorylation and the metabolism of glucose and glutamine, 2 major fuels for cancer cells. Therefore, the interplay between cancer metabolism and autophagy is a fundamental problem in biology with clear clinical relevance.
Personal comments I have always loved hiking and enjoying nature. Now living in beautiful San Diego, it is easier to find a little time to take a walk on the beach or just sit and watch the sunset. Since I moved to California, I have also discovered a new hobby here, hot yoga. It is great to release all the stress from the lab and give you balance.
Autophagy Volume 10 Issue 3
©2014 Landes Bioscience. Do not distribute.
actively involved in science communication. Explaining science in a simple way to nonexperts is a really interesting intellectual challenge, and I have published several scientific articles aimed at the general public. Since 2005 I have been an organizer of the Euroscience Open Forum (ESOF), a biannual conference that brings together scientists, policy makers, communicators, and the general public
David Rubinsztein Email: [email protected] If you could meet any scientist, currently living or from the past, who would it be and why? Leonardo da Vinci. He was not only an extraordinary artist, but a remarkable polymath in fields as diverse as mathematics, music, anatomy and engineering. In his time, he must have had a fascinatingly broad vision of the world. I suspect he was a super-genius who would have had the capacity to rapidly integrate knowledge of new fields and spot key questions.
Downloaded by [50.201.204.73] at 00:01 06 November 2015
Why do you study autophagy? It is a process that is likely to have importance in a range of physiological and disease processes.
Research focus Autophagy and neurodegeneration
its
relationship
to
Model system Cells (primary cells and cell lines); Drosophila; zebrafish, mouse models
What do you think are key questions in the autophagy field? How are autophagosomes formed? What are the functions of the ATG proteins? Can autophagy modulators be harnessed effectively for therapeutic objectives?
Education and career 1986, MB ChB, University of Cape Town, South Africa. 1988, BSc, medical biochemistry, University of Cape Town. 1989–1992, PhD, Medical Research Council/University of Cape Town Unit for the Cell Biology of Atherosclerosis, University of Cape Town, Department of Medical Biochemistry; advisor: Professor Denys van der Westhuyzen. 1993– 1998, senior registrar, Genetic Pathology, Addenbrooke’s Hospital Cambridge. 1996, Diploma of the Royal College of Pathologists, UK. 1997, member of the Royal College of Pathologists, Certificate of Completion of Specialist Training (clinical cytogenetics and molecular genetics). 1998–2002, Glaxo Wellcome Research Fellow/Honorary Consultant in Medical Genetics, University of Cambridge, UK. 2002–2011, Wellcome Trust Senior Research Fellow in Clinical Science/
www.landesbioscience.com
What do you hope to achieve in your scientific career? Make a discovery that can ultimately lead to benefits for people.
Is there a key experiment/finding that stands out in your mind with regard to autophagy? There has been tremendous progress in the autophagy field in the past 15 years, with many key findings, which have provided the foundations to our current work. One critical discovery from Yoshimori Ohsumi and colleagues was the correlation between LC3-II levels and autophagosomes. Prior to this, it was very difficult to measure autophagy activity and autophagosome formation, a critical requirement for being able to understand the relevance of autophagy.
If you could start over and choose a different career, what would it be? I feel very lucky, since I love my job. It is challenging and fulfilling. I am not sure I would be as happy in another career.
What one scientific discovery do you wish you had made? We have been trying hard to develop assays for autophagic flux that are more sensitive and robust than the conventional assays in wide use. These have been frustratingly unsuccessful. If we had developed such assays, then I think we would be able to understand more about autophagy regulation, and autophagic functions in health and disease.
Personal comments I am lucky to have a wife and 3 children who support my career. I am a keen amateur musician and enjoy playing the cello and piano. Like science, where one keeps on searching for answers and then the next set of answers to the questions that have emerged, there is no such thing as a perfect performance or interpretation of a piece of music. In both pursuits, one keeps on refining one’s “model.”
Autophagy 395
©2014 Landes Bioscience. Do not distribute.
Honorary Consultant in Medical Genetics, University of Cambridge. 2003–2005, reader in Molecular Neurogenetics, University of Cambridge. 2004, fellow of the Academy of Medical Sciences. 2005, fellow of the Royal College of Pathologists. 2005, Professor of Molecular Neurogenetics, University of Cambridge. 2012, Wellcome Trust Principal Research Fellow. 2012–present, deputy director, Cambridge Institute for Medical Research, UK.
Miklós Sass Research focus Genetic and hormonal regulation of autophagy in insects
Model system Previously I studied the autophagic process in the larval organs of Lepidopteran insects. Now, we work on Drosophila melanogaster.
Downloaded by [50.201.204.73] at 00:01 06 November 2015
Education and career 1971, MD, Eötvös Loránd University (ELTE), Budapest, Hungary. 1973, Dr Univ, comparative endocrinology, ELTE. 1984, PhD, cell biology, Hungarian Academy of Sciences (HAS); advisor: Prof János Kovács. 1995, Dr Habil, ELTE. 2005, DSc, HAS. 1998–present, professor, Department of Anatomy, Cell, and Developmental Biology, ELTE. 1996–2010, head of the Department of Anatomy, ELTE. 1999–2008, director, Institute of Biology, ELTE. 1991–1994, associate professor, Insect Biotech Canada, Department of Zoology, University of Western Ontario, London, Canada. 1999, visiting professor, Instituite of Low Temperature Sciences, Hokkaido University, Sapporo, Japan.
techniques and combined them with genetic methods to study the molecular mechanisms and regulatory processes of autophagy in detail. We performed a screen on public P-element mutant collections to identify and characterize novel autophagy-related genes in the fruitfly (Drosophila melanogaster). Our studies on these loss-of-function mutants prove the essential role of identified genes in autophagic machinery. Thus, this genetic model system is particularly attractive for studying molecular mechanisms underlying autophagy. Beyond the identification of novel autophagy genes in a multicellular organism, we intend to deal with the creation of signaling networks and cellular pathways that regulate and execute autophagy. Since the known autophagy genes are evolutionarily well conserved, our vision is that the discovery of new players of the regulatory network and molecular machinery of autophagy might represent new targets for drug design and might help us to combat human disorders accompanied with cell loss (e.g., neurodegenerative disorders, cerebrovascular and myocardial stroke), cancer, and aging.
Why do you study autophagy? I study autophagy to understand the molecular mechanisms and the regulatory networks of the cellular remodeling and cell death that occur during embryonal and postembryonal development. In the course of insect metamorphosis all of the cells of larval organs decompose and autophagy has an essential role in this process. My first studies focused on the hormonal regulation of autophagy and the activity of lysosomal enzymes in the larval fat body cells in Lepidopteran insects (Mamestra and Pieris brassicea). In Canada I worked on the molecular signals that direct the epidermal proteins of Calpodes ethlius to their physiologically correct directions. In this period I learned all of the available methods in molecular biology. Returning to Hungary I introduced these
396
What do you think is a key question in the autophagy field? Autophagy acts as a cytoprotective mechanism in certain physiological conditions. It promotes cell survival by degradation of macromolecules and cell organelles. The products of breakdown can then be released back into the cytosol and utilized for synthetic processes and to supply the cell with energy. On the one hand, autophagy eliminates damaged organelles, oxidized, long-lived, misfolded, or aggregated macromolecules, saving the intact parts of the cytoplasm. On the other hand, autophagy represents type II programmed cell death and has an essential role in targeted decomposition of well-defined cells, tissues, and organs during development. To
understand the mechanism of the decision on cell fate and on the role of autophagy is the most exciting question for me.
Is teaching a substantial part of your current position? As a professor in the Department of Anatomy, Cell, and Developmental Biology I do teach quite a lot, including classes related to comparative anatomy, molecular cell biology, and developmental biology, at BSc, MSc, and PhD levels. Of course, there is a mutual benefit between my teaching and my research work. I was the supervisor of 12 PhD students and more than 30 MSc students.
Personal comments Aside from work, when I was younger I used to do various sport activities. I was an active handball player, and later on I loved sailing, horse riding, and motocycling. Now, traveling and driving in Hungary and abroad, visiting Natural Parks, fishing, birdwaching, and nature photography are my favorite outdoor activities. At home I breed tropical fishes and read classic and contemporary literature, mainly novels to refresh my mind. I love the fine arts. I visit as many art exhibitions in Hungary and abroad as I can.
Autophagy Volume 10 Issue 3
©2014 Landes Bioscience. Do not distribute.
Email: [email protected]
ISSN: 1554-8627 (Print) 1554-8635 (Online) Journal homepage: http://www.tandfonline.com/loi/kaup20
Autophagy researchers To cite this article: (2014) Autophagy researchers, Autophagy, 10:3, 393-396, DOI: 10.4161/ auto.27581 To link to this article: http://dx.doi.org/10.4161/auto.27581
Published online: 17 Jan 2014.
Submit your article to this journal
Article views: 156
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kaup20 Download by: [50.201.204.73]
Date: 06 November 2015, At: 00:01
autophagy community
cell cycle news & views
Autophagy 10:3, 393–396; March 2014; © 2014 Landes Bioscience
Autophagy researchers Patricia Boya
Research focus I want to understand why the process of autophagy is essential to maintain cellular homeostasis and determine its role in animal physiology and pathology.
Model system We use the retina as our model system, which provides us with a window into the brain, and we perform in vivo studies using autophagy-deficient mice.
Education and career 2000, PhD, cell biology, University of Navarra, Spain; advisors: María Pilar Civeira and Esther Larrea. 2001–2004, postdoctoral researcher, Centre National de la Recherche Scientifique (CNRS), Paris, France; advisor: Guido Kroemer. 2005, postdoctoral researcher, University of Cambridge, UK; advisor: Aviva Tolkovsky. 2005–2009, Ramón y Cajal Scientist, Centro de Investigaciones Biológicas-Consejo Superior de Investigaciones Científicas (CIBCSIC), Madrid, Spain. 2009–present, staff scientist, CIB-CSIC.
Why do you study autophagy? While studying the role of lysosomes in apoptosis as a postdoctoral researcher, I found that lysosomal damage and subsequent permeabilization preceded cell death. I observed that cell death was associated with autophagosome accumulation, a phenotype indicative of
autophagic cell death. However, blockade of autophagy in these cells fails to prevent cell death and even increases it. Although these results were puzzling at first, I realized after attending the first Gordon Research Conference on Autophagy in Health, Development, and Disease in 2003 that by causing lysosomal damage I was blocking the final steps of autophagy. These results demonstrated that cells require functional autophagy to survive in normal and nutrient-deprived conditions, and provided the first evidence of a cytoprotective role of autophagy in mammalian cells. Currently I am interested in understanding the physiological roles of autophagy as well as its role in disease. In my lab, we are investigating the contribution of autophagy to the development of the nervous system, using the retina as a model. We want to unravel the relationship between autophagy and basic processes such as the cell cycle, cell differentiation, and cell death, and determine how intercellular crosstalk regulates tissue homeostasis. We have demonstrated that the maintenance of ATP levels by autophagy is essential for eliminating apoptotic cells during cell death associated with retinal neurogenesis. We are currently studying retinal development in knockout mice that lack specific autophagy regulators. As autophagy is a relatively new field, many of the necessary analytical tools are still being developed. Given that we mainly work in vivo, we are currently developing automated algorithms to quantify autophagic flux by image analysis in tissue. We also wish to understand why so many pathological processes, (e.g., cancer, neurodegenerative conditions) involve autophagy dysregulation. We have demonstrated that autophagy plays a cytoprotective role following axonal damage and in animal models of Parkinson disease. Moreover, we have described crosstalk between macroautophagy and chaperone-mediated autophagy during aging in the retina. Studies in our laboratory have also demonstrated that aging attenuates macroautophagy, an effect that is partially compensated by an increase in chaperone-mediated autophagy in specific retinal cell types.
We are currently searching for new therapies for retinal diseases including glaucoma and retinitis pigmentosa, a genetic retinal dystrophy that results in photoreceptor death, leading to blindness. I am a cofounder of ProRetina Therapeutics, a spin-off seeking to utilize some of the compounds that may modulate autophagy for clinical use.
What do you think is a key question in the autophagy field, and where do you think the field is heading? Autophagy is a very complex process that requires tight coordination. The identification of new regulators of this process will shed light on cell- and tissue-specific regulation of autophagy. It will be very interesting to identify the different roles of autophagy in maintaining homeostasis in tissues, and to determine how this recycling pathway participates in so many essential tasks, from the removal of cellular debris and damaged organelles to maintaining vision and participating in the immune response. Another emerging field is the complex crosstalk between different degradative pathways, as observed during aging and in autophagy-deficient mice.
What do you hope to achieve in your scientific career? I have been always interested in disease and the importance of understanding molecular mechanisms in order to develop new treatments to improve human health. I have several ongoing collaborations with biotech companies to find new therapeutic compounds that target autophagy. I study basic processes and try to apply this knowledge to the search for new therapies. Another goal is to maintain my curiosity and to continue enjoying research as much as I do now.
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 job does not require teaching but I enjoy it, and I currently teach some undergraduate and master’s courses. In addition, I am
www.landesbioscience.com Autophagy
393
©2014 Landes Bioscience. Do not distribute.
Downloaded by [50.201.204.73] at 00:01 06 November 2015
Email: [email protected]
cell cycle news & views
to discuss new discoveries and to influence science policy. In addition to my position on the steering committee, I have been involved in the organization of the Career Programme at ESOF, a series of events specifically aimed at young scientists. I am also very interested in scientific photography, and have had many images from my research projects published on journal covers.
Personal comments We have 2 children, with whom I love spending time. We like to be outdoors, watching birds and taking photographs to try to capture the beauty of nature. I am a very social person and enjoy good company and food. Cooking and performing experiments have a lot in common, and now that I spend less time at the bench, cooking provides me with a way to relax.
Maria T Diaz-Meco Email: [email protected]
Downloaded by [50.201.204.73] at 00:01 06 November 2015
Research focus Nutrient sensing in the regulation of cell growth and metabolism
Model system In vivo knockout mouse models, and human cancer and normal cell lines
Education and career 1988, BS, chemistry, University of Madrid, Spain. 1991, PhD, biochemistry and cellular and molecular biology, University of Madrid; advisor: Jorge Moscat. 1991–1996, postdoctoral scholar, Center of Molecular Biology “Severo Ochoa” Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. 1996–2003, assistant professor, Center of Molecular Biology “Severo Ochoa” CSIC. 2003–2006, associate professor, Center of Molecular Biology “Severo Ochoa” CSIC. 2006–2010, associate professor, Department of Cancer and Cell Biology, University of Cincinnati, OH, USA. 2010–2011, professor, Department of Cancer and Cell Biology, University of Cincinnati. 2011–present, professor, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
Why do you study autophagy? My interest in autophagy stems from my work on SQSTM1/p62, a signaling hub and also a cellular metabolic switch in autophagy. Since its initial discovery by our laboratory as an interacting partner of the aPKCs/atypical protein kinase Cs, SQSTM1 has emerged as a key molecule in the control of cell growth, cancer, and metabolic homeostasis. This multifunctional role is accounted for by its ability to bind other critical intermediaries through its multidomain organization. In this regard, its interaction with TRAF6 serves to activate NFKB, further emphasizing its role in cancer
394
and inflammation. Recently, through an unbiased proteomic approach, we have found that SQSTM1 binds RPTOR/raptor, and in complex with TRAF6 is an integral part of MTORC1 in the nutrient sensing response. Interestingly, SQSTM1 is subject to constant degradation via autophagy due to its binding to LC3 through a well-defined sequence motif in SQSTM1 termed the LIR. Since MTORC1 is a negative modulator of autophagy, these findings establish SQSTM1 as a key node of control of nutrient sensing and autophagy through its interactions with MTORC1 and LC3. This is of special relevance in light of the proposed role of SQSTM1 as a receptor in selective autophagy for the delivery of polyubiquitinated proteins and damaged organelles, such as mitochondria, into the autophagy proteolytic pathway. Thus, in addition to its signaling function, SQSTM1 can also play an essential role in cellular detoxification by maintaining low levels of misfolded proteins and damaged mitochondria, thus ensuring low levels of toxic ROS and a healthy metabolism. All these functions are critical for cell survival and tumor initiation and progression, which points to SQSTM1 as an important node for cancer and metabolic homeostasis. Therefore, I think that studying SQSTM1 using relevant in vivo models we will be able to unravel the intricacies of metabolic reprogramming in cancer and other diseases, which will inevitably result in the identification of novel and more selective therapeutic targets.
What do you think is a key question in the autophagy field? Finding the molecular mechanisms that govern the interplay of autophagy and MTOR signaling, and identifying the direct sensors of nutrients that mediate these signals would be
crucial to a better understanding of cancer cell metabolic reprogramming, and to design potential therapeutic interventions in the MTOR pathway. An additional key question remains the role of autophagy in cancer and its connection with cancer metabolism. It is becoming apparent that the ability of autophagy to maintain the quality control of mitochondria in the stressed cell perhaps through SQSTM1 is central to the regulation of oxidative phosphorylation and the metabolism of glucose and glutamine, 2 major fuels for cancer cells. Therefore, the interplay between cancer metabolism and autophagy is a fundamental problem in biology with clear clinical relevance.
Personal comments I have always loved hiking and enjoying nature. Now living in beautiful San Diego, it is easier to find a little time to take a walk on the beach or just sit and watch the sunset. Since I moved to California, I have also discovered a new hobby here, hot yoga. It is great to release all the stress from the lab and give you balance.
Autophagy Volume 10 Issue 3
©2014 Landes Bioscience. Do not distribute.
actively involved in science communication. Explaining science in a simple way to nonexperts is a really interesting intellectual challenge, and I have published several scientific articles aimed at the general public. Since 2005 I have been an organizer of the Euroscience Open Forum (ESOF), a biannual conference that brings together scientists, policy makers, communicators, and the general public
David Rubinsztein Email: [email protected] If you could meet any scientist, currently living or from the past, who would it be and why? Leonardo da Vinci. He was not only an extraordinary artist, but a remarkable polymath in fields as diverse as mathematics, music, anatomy and engineering. In his time, he must have had a fascinatingly broad vision of the world. I suspect he was a super-genius who would have had the capacity to rapidly integrate knowledge of new fields and spot key questions.
Downloaded by [50.201.204.73] at 00:01 06 November 2015
Why do you study autophagy? It is a process that is likely to have importance in a range of physiological and disease processes.
Research focus Autophagy and neurodegeneration
its
relationship
to
Model system Cells (primary cells and cell lines); Drosophila; zebrafish, mouse models
What do you think are key questions in the autophagy field? How are autophagosomes formed? What are the functions of the ATG proteins? Can autophagy modulators be harnessed effectively for therapeutic objectives?
Education and career 1986, MB ChB, University of Cape Town, South Africa. 1988, BSc, medical biochemistry, University of Cape Town. 1989–1992, PhD, Medical Research Council/University of Cape Town Unit for the Cell Biology of Atherosclerosis, University of Cape Town, Department of Medical Biochemistry; advisor: Professor Denys van der Westhuyzen. 1993– 1998, senior registrar, Genetic Pathology, Addenbrooke’s Hospital Cambridge. 1996, Diploma of the Royal College of Pathologists, UK. 1997, member of the Royal College of Pathologists, Certificate of Completion of Specialist Training (clinical cytogenetics and molecular genetics). 1998–2002, Glaxo Wellcome Research Fellow/Honorary Consultant in Medical Genetics, University of Cambridge, UK. 2002–2011, Wellcome Trust Senior Research Fellow in Clinical Science/
www.landesbioscience.com
What do you hope to achieve in your scientific career? Make a discovery that can ultimately lead to benefits for people.
Is there a key experiment/finding that stands out in your mind with regard to autophagy? There has been tremendous progress in the autophagy field in the past 15 years, with many key findings, which have provided the foundations to our current work. One critical discovery from Yoshimori Ohsumi and colleagues was the correlation between LC3-II levels and autophagosomes. Prior to this, it was very difficult to measure autophagy activity and autophagosome formation, a critical requirement for being able to understand the relevance of autophagy.
If you could start over and choose a different career, what would it be? I feel very lucky, since I love my job. It is challenging and fulfilling. I am not sure I would be as happy in another career.
What one scientific discovery do you wish you had made? We have been trying hard to develop assays for autophagic flux that are more sensitive and robust than the conventional assays in wide use. These have been frustratingly unsuccessful. If we had developed such assays, then I think we would be able to understand more about autophagy regulation, and autophagic functions in health and disease.
Personal comments I am lucky to have a wife and 3 children who support my career. I am a keen amateur musician and enjoy playing the cello and piano. Like science, where one keeps on searching for answers and then the next set of answers to the questions that have emerged, there is no such thing as a perfect performance or interpretation of a piece of music. In both pursuits, one keeps on refining one’s “model.”
Autophagy 395
©2014 Landes Bioscience. Do not distribute.
Honorary Consultant in Medical Genetics, University of Cambridge. 2003–2005, reader in Molecular Neurogenetics, University of Cambridge. 2004, fellow of the Academy of Medical Sciences. 2005, fellow of the Royal College of Pathologists. 2005, Professor of Molecular Neurogenetics, University of Cambridge. 2012, Wellcome Trust Principal Research Fellow. 2012–present, deputy director, Cambridge Institute for Medical Research, UK.
Miklós Sass Research focus Genetic and hormonal regulation of autophagy in insects
Model system Previously I studied the autophagic process in the larval organs of Lepidopteran insects. Now, we work on Drosophila melanogaster.
Downloaded by [50.201.204.73] at 00:01 06 November 2015
Education and career 1971, MD, Eötvös Loránd University (ELTE), Budapest, Hungary. 1973, Dr Univ, comparative endocrinology, ELTE. 1984, PhD, cell biology, Hungarian Academy of Sciences (HAS); advisor: Prof János Kovács. 1995, Dr Habil, ELTE. 2005, DSc, HAS. 1998–present, professor, Department of Anatomy, Cell, and Developmental Biology, ELTE. 1996–2010, head of the Department of Anatomy, ELTE. 1999–2008, director, Institute of Biology, ELTE. 1991–1994, associate professor, Insect Biotech Canada, Department of Zoology, University of Western Ontario, London, Canada. 1999, visiting professor, Instituite of Low Temperature Sciences, Hokkaido University, Sapporo, Japan.
techniques and combined them with genetic methods to study the molecular mechanisms and regulatory processes of autophagy in detail. We performed a screen on public P-element mutant collections to identify and characterize novel autophagy-related genes in the fruitfly (Drosophila melanogaster). Our studies on these loss-of-function mutants prove the essential role of identified genes in autophagic machinery. Thus, this genetic model system is particularly attractive for studying molecular mechanisms underlying autophagy. Beyond the identification of novel autophagy genes in a multicellular organism, we intend to deal with the creation of signaling networks and cellular pathways that regulate and execute autophagy. Since the known autophagy genes are evolutionarily well conserved, our vision is that the discovery of new players of the regulatory network and molecular machinery of autophagy might represent new targets for drug design and might help us to combat human disorders accompanied with cell loss (e.g., neurodegenerative disorders, cerebrovascular and myocardial stroke), cancer, and aging.
Why do you study autophagy? I study autophagy to understand the molecular mechanisms and the regulatory networks of the cellular remodeling and cell death that occur during embryonal and postembryonal development. In the course of insect metamorphosis all of the cells of larval organs decompose and autophagy has an essential role in this process. My first studies focused on the hormonal regulation of autophagy and the activity of lysosomal enzymes in the larval fat body cells in Lepidopteran insects (Mamestra and Pieris brassicea). In Canada I worked on the molecular signals that direct the epidermal proteins of Calpodes ethlius to their physiologically correct directions. In this period I learned all of the available methods in molecular biology. Returning to Hungary I introduced these
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What do you think is a key question in the autophagy field? Autophagy acts as a cytoprotective mechanism in certain physiological conditions. It promotes cell survival by degradation of macromolecules and cell organelles. The products of breakdown can then be released back into the cytosol and utilized for synthetic processes and to supply the cell with energy. On the one hand, autophagy eliminates damaged organelles, oxidized, long-lived, misfolded, or aggregated macromolecules, saving the intact parts of the cytoplasm. On the other hand, autophagy represents type II programmed cell death and has an essential role in targeted decomposition of well-defined cells, tissues, and organs during development. To
understand the mechanism of the decision on cell fate and on the role of autophagy is the most exciting question for me.
Is teaching a substantial part of your current position? As a professor in the Department of Anatomy, Cell, and Developmental Biology I do teach quite a lot, including classes related to comparative anatomy, molecular cell biology, and developmental biology, at BSc, MSc, and PhD levels. Of course, there is a mutual benefit between my teaching and my research work. I was the supervisor of 12 PhD students and more than 30 MSc students.
Personal comments Aside from work, when I was younger I used to do various sport activities. I was an active handball player, and later on I loved sailing, horse riding, and motocycling. Now, traveling and driving in Hungary and abroad, visiting Natural Parks, fishing, birdwaching, and nature photography are my favorite outdoor activities. At home I breed tropical fishes and read classic and contemporary literature, mainly novels to refresh my mind. I love the fine arts. I visit as many art exhibitions in Hungary and abroad as I can.
Autophagy Volume 10 Issue 3
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