Who or what first sparked your interest in science?
I actually started developing an interest in science as a child through helping my father on our family farm. I don’t think many people appreciate the scientific knowledge that is required for modern farming operations. When school was out for the summer, I would help him with tasks such as soil sample collection, assembling irrigation systems, and assessing disease within our crops. It’s through him that I first learned about things like acids, bases, pH, hydrology, and plant biology. I can’t imagine a better classroom or tutor.
Is there a specific mentor that inspired you to become a scientist or that has significantly influenced your goals in research
I’ve had the benefit of training under some incredible mentors as a graduate student and postdoc, each of whom has been instrumental in my decision to become a scientist. All shared an infectious passion for science and were motivated by a desire to help and teach others. Although scientific research can be challenging at times, I hope that I always carry their enthusiasm and dedication in my scientific pursuits and have the opportunity to pass along some of the things I learned under their mentorship.
How instrumental have been mentor and departmental support to your success in identifying and securing funding?
The UCSF Office of Career & Professional Development (OCPD) and my mentor, Jay Debnath, both helped a great deal with identifying and successfully capturing external funding. The OCPD routinely posts notices for various fellowship competitions on their website, and that’s how I learned about awards that I was eligible for as an international scholar from Canada. During the preparation of my fellowship applications, I routinely met with my mentor for his opinions on scientific ideas as well as grant writing advice. Surely, without their help I wouldn’t have found as much success in these award competitions.
How do you tackle questions from friends and family to ensure that they appreciate the value and potential impact of your work?
This has been a little easier of late since Yoshinori Ohsumi won a Nobel Prize for the discovery of autophagy. However, most people appreciate that the cells within our body frequently accrue damage from things like UV radiation or excessive heat and that mechanisms such as autophagy must exist to help remove and recycle compromised cellular components to keep them functioning properly. I like to use the analogy that autophagy is the garbage disposal pathway of our cells; it’s easy to imagine the consequences of not removing the trash from our homes, whereas for our cells, failure to dispose of trash contributes to processes such as aging and diseases like Parkinson’s.
Based on your experience pursuing research training in both Canada and the United States, can you highlight some of the main advantages and caveats of the main funding agencies, CIHR vs. NIH?
In my limited experience, I find a lot of structural similarities between the Canadian Institute of Health Research (CIHR) and National Institute of Health (NIH) funding agencies. I suspect this is because the CIHR is partly modeled upon the NIH. Both are subdivided into smaller institutes focused on specific areas of research such as cancer and aging. Grants or fellowship applications are submitted online to these smaller institutes for review by expert panels specific to the area of intended research. The applications themselves also have many of the same components and requirements, and success rates generally vary between 10-20% depending upon the current government and economy. More recently in Canada, funding rates have dipped closer to this 10% mark which is somewhat discouraging, but this may improve with a newly elected government and changes afoot in the CIHR. One of the biggest differences between the two funding agencies is the monetary value of grants. CIHR grants and fellowships generally have lower values, in part, because healthcare is free and isn’t paid by the employer. Nevertheless, NIH grants frequently still give labs more money even when you take health insurance into account. I believe that this funding discrepancy gives labs in the United States a greater cushion to pursue high risk and high reward studies which helps push the boundaries of science. Neither the CIHR or NIH is perfect and hopefully through the coordinated efforts of government officials and scientists these agencies continue to refine their mechanisms and policies for the benefit of everyone.
In your current postdoctoral position, you contributed opinion pieces to Developmental Cell Previews and Cell Cycle News & Views. What advice can you share with your peers about how to pursue such opportunities?
To be honest, my mentor Jay Debnath frequently receives requests to write opinion pieces for journals and he will ask his trainees whether they would like to contribute. I try to take advantage of these opportunities because it gives me practice writing and also helps bolster my CV. I think everyone should accept these invitations because they really help to improve your writing skills and maintain continuity in your publication record.
Which training activities (e.g., teaching, mentoring and committee services) have you found more rewarding and critical for your scientific development?
As a postdoc, I’ve had the opportunity to mentor a number of excellent trainees, teach undergraduates, and serve on hiring and fellowship review committees. Certainly, the hiring and fellowship review committees were very enlightening, but I found teaching and mentoring to be the most rewarding and beneficial for my development. These opportunities helped me hone my communication skills and further develop as a leader. Teaching and mentoring are great ways to learn about your own boundaries of understanding on a specific topic or concept because inevitably you will be asked something that you can’t answer. However, the most rewarding aspect has been the relationships that have emerged from these experiences. A number of mentees have either joined our lab or continue to stay in touch and helped me in my own research through collaboration or their insights from another field.
In the recent ASCB Conference (2017), you talked about your most recent findings which connect the autophagy machinery to the process of RNA-binding protein sorting to extracellular microvesicles. Could you highlight some of the most important findings?
Although I can’t divulge very much because we have a manuscript on these studies currently in revision, we believe that we have uncovered a connection between the autophagy machinery and the packaging of proteins into extracellular microvesicles or exosomes. One of the big unknowns in the field of exosomes are the mechanisms by which cargo is selectively loaded into these tiny membrane enclosed sacs for release outside of the cell. Intriguingly, the autophagy pathway has machinery that does precisely this; except that during autophagy cargo is typically loaded into autophagosomes and destined for lysosomal degradation. Through a novel proteomic approach designed to identify substrates of an emerging pathway known as autophagy-dependent unconventional secretion, we discovered a number of key autophagy proteins outside the cell, as well as proteins known to be packaged into exosomes. Remarkably, when we attenuated secretion of these autophagy proteins this also affected the packaging of specific proteins into exosomes. We are very excited about this study and its implications for the fields of autophagy and extracellular microvesicles. Hopefully it will be published in the near future.
Autophagy, as a homeostatic mechanism is a cell-autonomous process, but your work highlights its potential impact at the organismal level. What are the physiological and pathophysiological consequences of a crosstalk between the autophagy machinery and microvesicle loading?
This is an excellent question and something we are actively pursuing. However, we currently don’t have any concrete answers and therefore I can only speculate. Indeed, accumulating evidence from organisms such as C. elegans and mice indicate that autophagy also has important non-cell autonomous functions. For example, autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor, which is required for platelet adhesion to the injured blood vessel wall. In normal physiology, autophagy-dependent packaging of proteins into extracellular microvesicles may be involved with intercellular signaling and communication that coordinates systemic responses or organismal behaviors that serve to maintain homeostasis. However, given the important functions of autophagy in clearing damaged proteins and organelles, it’s also easy to imagine how dysfunction in the autophagy pathway could lead to the pathogenic spread of harmful molecules between cells. Certainly, there is much left to understand about this exciting new role for the autophagy machinery.
Select Publications by Dr. Andrew Leidal:
Roy S, Leidal A, Ye J, Ronen SM, Debnath J. Autophagy-Dependent Shuttling of TBC1D5 Controls Plasma Membrane Translocation of GLUT1 and Glucose Uptake. Mol Cell. 2017 Jul 06; 67(1):84-95.e5. PMID: 28602638.
Rose JC, Huang PS, Camp ND, Ye J, Leidal A, Goreshnik I, Trevillian BM, Dickinson MS, Cunningham-Bryant D, Debnath J, Baker D, Wolf-Yadlin A, Maly DJ. A computationally engineered RAS rheostat reveals RAS-ERK signaling dynamics. Nat Chem Biol. 2017 Jan; 13(1):119-126. PMID: 27870838.
Leidal AM, Cyr DP, Hill RJ, Lee PW, McCormick C. Subversion of Autophagy by Kaposi's Sarcoma-Associated Herpesvirus Impairs Oncogene-Induced Senescence. Cell Host Microbe. 2016 Jun 08; 19(6):901. PMID: 27281574.
Kenific CM, Stehbens SJ, Goldsmith J, Leidal A, Faure N, Ye J, Wittmann T, Debnath J. NBR1 enables autophagy-dependent focal adhesion turnover. J Cell Biol. 2016 Feb 29; 212(5):577-90. PMID: 26903539; PMCID: PMC4772495.
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