Keywords: :
Sabine Hilfiker
Email: [email protected]
Research focus
Understanding the effects of Parkinson disease (PD)-associated proteins on autophagy and lysosomal homeostasis; links of autophagy to other intracellular trafficking pathways.
Model system
Mammalian cells, fibroblasts from control and PD patients, and human pathological specimens.
Education and career
1998, PhD, neuroscience, Rockefeller University, New York, NY, USA; advisor: Paul Greengard; 1998–2000, postdoctoral fellow, Rockefeller University; advisor: Paul Greengard; 2000–2003, BBSRC David Phillips Research Fellow, Manchester University, UK; 2003–2009, Ramón y Cajal Fellow, CSIC, Spain; 2009–present, principal investigator, CSIC.
Why do you study autophagy?
Our laboratory is studying the molecular and cellular mechanisms underlying PD. We mainly focus on trying to understand the normal and pathological function of a large protein kinase called LRRK2, mutations in which comprise the most important genetic determinant of PD. During the course of our studies, we obtained evidence that pathogenic LRRK2 may impede autophagic flux in a manner dependent on acidic organelle calcium stores. Since then, we are interested in understanding this mechanism better, and identify targets (e.g., protein interactors or substrates) responsible for the observed changes. I found it relatively easy to enter the autophagy field. Even though a complex cell biological phenomenon, the published technical guidelines have allowed us to rapidly establish reproducible and relevant assays. Likewise, I encountered many researchers in the autophagy community willing to share tools and expertise, which has helped us tremendously to move our research forward in a competitive manner. My interest in the role that aberrant autophagy may play in neuronal dysfunction mediated by pathogenic LRRK2 continues to be a central aspect of the lab.
What do you think are key questions in the autophagy field?
Questions which are related to both mechanistic and translational aspects. In my opinion, understanding of the overlapping and distinct mechanisms and triggers involved in the different types of autophagy (macroautophagy, chaperone-mediated autophagy, microautophagy, crinophagy), to elucidate why and when a given mechanism of autophagy is used over another, and how they interrelate with each other. Also, I think it is important to understand the links of autophagy to other cellular mechanisms; for example, how defects in endocytosis or retromer-mediated trafficking have an impact on autophagy and vice versa, how altered autophagy may contribute to exosome release and transmission of several neurodegenerative diseases, as has been recently described, how alterations in intracellular calcium stores may affect autophagy, or how enhancing lysosomal function may revert the above-mentioned pathway deficits. Other key questions I think relate to whether we can apply this knowledge to develop drugs to treat various diseases. For example, can autophagy modulators be beneficial for distinct neurodegenerative disorders, and what pathways are best targeted? Or, how do autophagy modulators regulate exosome release and thus transmission of a neurodegenerative disease state from cell to cell? There are some exciting data out there, but they need to be further validated and extended.
Is teaching a substantial part of your current position?
My position does not involve giving classes, but I enjoy lab-based teaching at all levels. Our lab hosts high school students, last-year university degree students, and summer exchange students. I think it is important to support and foster young people’s enthusiasm toward science, and have them transmit scientific ideas and concepts to our society.
Personal comments
I spend most of my free time with my family. I have 2 sons (8 and 14 years old), and love traveling. In the winter, we go skiing in the Sierra Nevada, in Granada or in the Swiss mountains (being Swiss I´d say there are no better slopes than Swiss slopes though), and in the summer we go sailing in the Mediteranean Sea. I keep pretending that when my kids are big, I´ll have more time to do the things I did have time to do before having kids, such as reading a good book or going to a movie or a concert. However, if I can choose between those activities and working some more, I think most of the time I would actually prefer the latter. So, having kids has turned out to be a good way for me to have a life outside the lab.
Vladimir Kirkin
Email: [email protected]
Research focus
Discovery of autophagy-modulating drugs and mechanisms of selective autophagy.
Model system
Cultured mammalian cells, patient-derived tissue, and animal models for human diseases.
Education and career
1997, MSc, University of Warwick, Coventry, UK; advisor: Dr Lynne Roberts. 2001, PhD, University of Karlsruhe, Karlsruhe, Germany; advisor: Dr Jonathan Sleeman. 2001–2006, postdoc, Georg-Speyer-Haus, Frankfurt, Germany; advisor: Dr Martin Zörnig. 2006–2008, postdoc, Institute of Biochemistry II, Goethe University Frankfurt, Germany; advisor: Dr Ivan Dikic. 2008–present, researcher and project manager, Merck Serono, Darmstadt, Germany.
Why do you study autophagy?
The lab of Ivan Dikic, which I joined in 2006, was interested in deciphering the role of ubiquitin-like proteins (UBLs) in cell signaling networks. Ivan’s original idea was to look into the noncovalent interactome of UBLs, at that time done mostly by yeast two-hybrid analyses, to get clues to the functions of these versatile proteins. Given a bunch of UBLs, I chose to work on LC3/Atg8 and ATG12, 2 novel UBLs, already known to play a role in autophagy. Discoveries made in Ivan’s lab following those screens and in collaboration with Terje Johansen, Masaaki Komatsu, Zvulun Elazar, and others—identification and characterization of selective autophagy receptors—made me fall for the beauty and meaningfulness of the autophagy pathway. This fascination about the pathway has kept me going ever since. The role of autophagy in human health and disease is another passion of mine deeply anchored in the dream of bringing a remedy to devastating diseases, such as cancer. This dream brought me to Merck Serono where I have worked for the past 5 years to translate results of basic autophagy research into viable therapeutic concepts.
What do you hope to achieve in your scientific career?
Working in the pharmaceutical industry, I look forward to the identification of potent and selective compounds modulating autophagy in a targeted way. I am keen to use such compounds to consolidate the therapeutic concept of targeting autophagy in human disease, and, further, to develop autophagy-modulating drugs that will be of benefit for patients. By performing basic and translational research and through collaboration with the autophagy community, I hope to provide a solid foundation for understanding the role of autophagy in human disease that will allow the development of effective and safe drugs in the future. My research toward understanding the mechanisms of selective autophagy in collaboration with Ivan Dikic, Christian Behrends, Vladimir Rogov, Volker Dötsch, and Terje Johansen, for instance, holds the promise of the identification of novel targets within the autophagy pathway, making future autophagy-modulating drugs more selective and hence having the potential for an improved therapeutic window.
Is there a key experiment/finding that stands out in your mind with regard to autophagy?
The seminal paper from Johansen’s lab, published in 2007 in The Journal of Biological Chemistry, undoubtedly was a cornerstone for the modern studies of selective autophagy in mammalian cells. In this paper, Pankiv et al. report on the first mammalian LC3/GABARAP-binding protein (SQSTM1/p62), identify the first LC3-interacting region (LIR), for the first time demonstrate LIR-dependent autophagic degradation, and establish the aggregate-promoting role of this prototypic autophagy receptor. In the same year, in a Cell paper, using in vivo models, Komatsu and colleagues provide independent evidence for the role of SQSTM1 in formation and autophagic clearance of protein aggregates.
Personal comments
Autophagy and music are tightly interlinked, as eloquently demonstrated by Dan Klionsky and Nobuo Munakata in their “Autophagy Suite” (Autophagy 2010; 6:679–85). No surprise that, being an inveterate autophagy researcher, I indulge in composing music. I write instrumental pieces and songs, which I occasionally perform for friends and song lovers from nonautophagic circles. For songs, I draw inspiration from the treasure trove of Russian literature (I spent my childhood in the Republic of Moldova). During my PhD project, I would write parodies of popular songs and perform them at the institute’s Christmas parties, filling in the gap for lagging breakthroughs in the lab. My life would be dull without my family: my wife, to whom I am indebted for love and support for the past 20 years, and two young daughters (Alisa and Polina). For some reason, “autophagy” is their favorite word too.
Ben Loos
Email: [email protected]
Research focus
Autophagic flux and cell death in neurodegeneration.
Model system
GT1-7, PC-12, SH-SY5Y, and stably expressing GFP-MEF cells, exposed to autophagy modulators and metabolic perturbations; tissue biopsy material.
Education and career
2009, PhD, physiological sciences, Stellenbosch University, Stellenbosch, South Africa; advisor: Anna-Mart Engelbrecht. 2010–2012, scientist and unit manager, Cell Imaging Unit, Central Analytical Facility, Stellenbosch University; advisor: Gary Stevens. 2012–present, lecturer and group leader, physiological sciences, Stellenbosch University.
Why do you study autophagy?
I am fascinated by this pathway, as it has so many facets that are related to fundamental cellular function: protein degradation, metabolism, and stress response to name a few. This makes this pathway unique and positions it for me as a “cell function hub” as well as a basal response scheme, affecting the cell’s ability to withstand or cope with stress. Its role in metabolism and protein degradation is so crucially linked to cellular homeostasis and viability, that it deserves all the possible attention.
What do you think is a key question in the autophagy field?
For me a key question in the field centers on autophagic flux and its relationship to cell death susceptibility. If I unpack this, then a very prominent key question is the challenge of measuring and finely controlling autophagic flux. As the field heads toward the clinical exploitation of the autophagic system, we need to be in a better position to answer questions like “how much autophagy, and applied for how long, will provide the desired outcome?” The outcome may be related to the extent of neuronal protein aggregate formation/clearance, the extent of cell survival in distressed/injured tissue or the degree of apoptosis induction in a tumor.
What do you hope to achieve in your scientific career?
My goal is to contribute significantly toward an understanding of autophagic flux in neuronal protein aggregate formation, and toward the accurate, controlled, and predictable exploitation of autophagy in the context of pathology. I am interested in how we can better measure flux, so that various fluxes can be probed against protein aggregate formation and neuronal toxicity. I often compare the autophagic measuring system of the future to the routine tests performed for measuring blood clotting parameters. That means we need standardized tools, units, and metrics for autophagic activity that are robust and reliable, in vitro as well as in vivo. One part of my research has therefore a systems and biophysics multidisciplinary angle, filling some of the gaps that a classical cell physiology approach may leave behind. I am moreover interested in the relationship between metabolite substrates, mitochondrial function, and autophagic flux. I hope to always encourage my students to tackle the important questions with the best suitable tools, to train them well, to be globally present, and to show that work is a fun place to be.
Is there a key experiment/finding that stands out in your mind with regard to autophagy?
The generation of the GFP-LC3 transgenic mouse by Mizushima, as well as the work by Singh and Cuervo on autophagy and lipid metabolism stand out for me, as they demonstrate fundamental roles, such as autophagy operating in a highly tissue-specific manner, with a clear and profound impact on cell metabolism.
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?
Yes, I teach the 3rd year undergraduate life science program on basic central nervous system physiology and protein metabolism as well as a block in the postgraduate course on neurodegeneration and integration. Both teaching environments are often inspirational, as new ideas and views have their platform and bring an additional “spin” to my research focus.
Personal comments
I am thrilled to know and to work with so many fantastic people in the field. I am married to an awesome wife and have a beautiful son (Joshua, 2). I have been “accused” of turning my son into a nerd, as he has his own light microscope. My hobbies are running, music by Bach, photography, and building exploded (i.e., disjointed and mounted) skull models from large mammals (the latter to the dismay of my wife, as the procedure can be rather smelly!).
Muriel Priault
Email: [email protected]
Research focus
My research interest is centered on the oncogene BCL2L1/Bcl-xL, and I endeavor to unravel the many ways this protein is used to sustain cell survival, including its ability to stimulate autophagy.
Model system
Cultured cancer and primary cells.
Education and career
1996–1997, master's degree, biochemistry, Université Bordeaux Ségalen, France; advisor: Dr S Manon; 1998–2001, PhD, biology and medical sciences, Institute of Cellular Biochemistry and Genetics (CNRS), Bordeaux, France; advisor: Dr S Manon; 2001–2003: junior postdoc researcher, Department of Cell Biology, Science III Geneva, Switzerland; advisor: Pr JC Martinou; 2003–2006: postdoctoral researcher, INSERM, Center for Cancer Research of Nantes; advivsor: FM Vallette; 2006–2007: postdoctoral researcher, Institute of Cellular Biochemistry and Genetics; advisor: Dr S Manon; 2007–present: CNRS researcher, Institute of Cellular Biochemistry and Genetics, team “mitochondria, stress, and cell deaths,” directed by Dr S Manon.
Why do you study autophagy?
When I started studying autophagy in 2001 during my first postdoc, almost nothing was known about how mitochondria are degraded in cells. So I addressed this question using mutant yeast cells that generate mitochondrial defects, to ask whether mitochondrial damage would be of use in monitoring a degradation process; it was actually the case and this process turned out to rely on autophagy. By the time of my second postdoc, it was becoming more and more obvious from the growing literature that a survival process like autophagy was bound to communicate with other processes governing cell fate, and since my PhD was on BCL2 family members and how they regulate apoptosis, I decided to investigate the crosstalk between apoptosis and autophagy, taking the oncogene BCL2L1 as the cornerstone of my study.
What do you think is a key question(s) in the autophagy field?
There are still so many open questions! Some relate to the exact steps that convert the induction signal into the piece-by-piece assembly of autophagosomes, and what fits their amount to the intensity of the initial signal, or is it their size that is adjusted to meet the initial demand? Another big question I have is how metabolism interconnects with autophagy regulation (in healthy cells as well as in cancer cells) and I just cannot get over the fact that in this field we modify the object we are trying to characterize, as the media composition we use already influences the metabolism of the cells we grow. That's Schrödinger's cat concept applied to biology: does the reality depend on who is observing it...
What do you hope to achieve in your scientific career?
I view science as a wonderful way to educate people and set them free from all forms of obscurity. I hope I live and work long enough to drive some students (even if it is just one) to constantly question what surrounds them and reject beliefs of any kind.
If you could meet any scientist, currently living or from the past, who would it be and why?
I wish I had met François Jacob, who was awarded the Nobel Prize for medicine in 1965 (with Lwoff and Monod) and is most famous for his work on the lactose operon. He is generally viewed as one of the founding fathers of molecular biology. Reading his book “La Statue Intérieure” when I was a teenager gave me the impetus to become a scientist. He unfortunately died in April 2013.
Personal comments
My hobbies are in line with the experimental work at the bench since I love to cook and bake. I just can't wait for my son to be old enough to share this other passion with him! I also enjoy jogging in the vineyards that surround the institute where I work. My favorite movies are “Love Actually,” “Paul,” and “H2G2.” My favorite books are from Dan Simmons.