Would you tell us what sparked your interest in basic science?
Of course, my high school project was on alcohols. But, it is not what you think right now... By researching the topic I was fascinated by the ability to predict physical-chemical properties of alcohols, like boiling and melting points, dependent on the length of aliphatic chains and even vs. odd number of carbons, saturated vs unsaturated, etc. From then on, it was all about molecules in motion for me.
You have made many significant discoveries in the process of Selective Autophagy. Is there one specific experiment or discovery you feel most proud of? An ‘aha moment’?
Yes, many a time, but specifically when we thought that perhaps, just perhaps, autophagy could capture invading microbes and kill them. This was what many consider our landmark paper in Cell in 2004. It was very clear and simple back then, and it was such an “aha moment”. The last one was in 2018 (the study was published in Molecular Cell a few months back) when we found that lysosomal damage controls mTOR and AMPK activity via galectins recognizing membrane tears, and that this signaling then activates autophagy as well as metabolically reprograms the cell. Still going over the beauty of that “aha moment”, as it too is simple and I think beautiful.
“..research is hard but intellectual rewards are hard to beat. Sometimes research is like art, and I often think of artists and their difficulties.”
Tell us more about the questions you and your lab are currently trying to answer and where you see your research moving in the future.
Right now, we are fascinated by the signaling that controls AMPK and mTOR. I think that the very upstream regulation of these systems responds to membrane integrity, i.e. not just nutrient and energy status.
Could you elaborate on the importance of your research for the ordinary citizen.
Degradation vs. biogenesis is the yin and the yang of life. We are stuck in our bodies so to speak, and the key question is how to remove and replace the older, no longer functioning parts from within. To know how to do that may hold secrets to longevity, quality of life, prevention and treatment of disease from head to toe. We hope that soon (not just some day) this research will make us healthier and happier. And then, we are aiming at big diseases as diverse as Alzheimer’s, Parkinson’s, diabetes, cancer on one end and tuberculosis, HIV and all sorts of inflammatory disease on the other. That is the beauty of autophagy as a drug target.
Lab photo from 2018 Spring ATG (autophagy traditional gatherings). From left: Suresh Kumar, Seong Won Choi, Yuexi Gu, Aurore Claude-Taupen, Jingyue Jia, Lee Allers, Bhawana Bissa, Michal Mudd.
Your research has advanced our understanding of the connection between Galectins and Autophagy for endomembrane homeostasis. Is there one experiment or discovery that you feel most proud of?
I think the most rewarding moment was when we put our study you are referring to, to the ultimate test of unbiased analysis after the fact. While the paper was in revision, we carried out a BioID dynamic LC-MS/MS proteomic analysis in cells subjected to membrane damage and to my biggest surprise all the components of the galectin 8-mTOR system and their behavior were completely validated. Even more surprising and paradoxically satisfying was that we did not find any new components (which, quite frankly, I fully expected) relative to what we already discovered. In sum, this showed to us that we did not miss something potentially more important. An interesting twist – since proteomic studies often lead a study, in this case it was more of a validation after the fact. I still marvel over my reaction to the mass spec findings with feelings of validation instead of a disappointment with not finding additional components.
Your discoveries expand the significance of Galectins in Autophagy to much more than “tags” alerting of membrane damage. What implications do you foresee for strategies targeting diseases such as cancer?
Cancer cells grow past authorized limits and that is in essence the definition of cancer. The two regulators of autophagy, mTOR and AMPK, which now we know are subject to control by galectins in response to endomembrane damage, are also key regulators of general metabolism underpinning the ability to grow and spread. Cancer cells depend on altered regulation, or rather deregulation of mTOR and AMPK. We think that the link between endomembrane damage and cell metabolism in general is a new, unexplored area and we hope it will arm us with new approaches to cancer therapy. Imagine an ability to subvert cancer cells growth by damaging lysosomal membranes.
Tell us why you research? What motivates you to keep forging ahead?
To this day, I remain curios as a child. Maybe it is an immature state, but I fully embrace it and enjoy it. The thrill of discovery is like no other. This keeps me through more mundane and sometimes tedious aspects of doing research. In sum, research is hard but intellectual rewards are hard to beat. Sometimes research is like art, and I often think of artists and their difficulties.
What advice would you give to early career scientists interested in pursuing tenure track positions?
Science is not just another job. It is a privilege. We often complain about difficulties, but research in the past used to be reserved for the independently wealthy who could fund pursuits of their intellectual curiosity, or to those few supported by the wealthy. Modern societies allow us, with appropriate schooling and training, to get to that position in a more democratic way. Enjoy the possibilities and consider yourselves privileged. Another bit is not to worry that it is very competitive out there. Be happy that there are many, many smart people out there, we need every one of them for various scientific and political reasons. Consider your career in science not just as an opportunity but also as your societal duty.
And finally, if you could meet any scientist from the past, who would you meet and why?
Oh my, this is a spectacular question, but I better be careful…, Can you please arrange to meet Alfred Wallace, the less known contemporary of Darwin with identical ideas. I love SCUBA diving and Wallace is a hero of mine, by recognizing the diversity of marine life and defining the biocline in Indonesia.
While you are at it, can I please meet Aristotle, Imhotep, Galileo, Newton, Bernoulli, Boltzmann, Maxwell, Pauling, (I met Crick), and Marie Curie, and …
Back to Faculty Interview Archive