Interview with an early-career scientist: Dr Nadav Weinstock
Hear from the lead author of a landmark paper in Neuron about his research into Krabbe Disease
This July, Dr. Laura Feltri’s team at the University of Buffalo published a landmark paper in Neuron "Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction" (PMID: 32375064) detailing new insights into the pathological mechanisms of Krabbe disease. Proteintech’s Dr Rebecca Northeast, spoke to the lead author Dr Weinstock about this work and his experience as an early-career scientist.
Firstly, thank you for your time and congratulations on your recent paper in Neuron! Can you start by telling me a bit about yourself, your background, and how you ended up in the lab of Dr. Feltri?
"Sure, no problem! I am an MD/PhD student at the University at Buffalo in my final year of medical school. I completed my PhD in neuroscience, working on Krabbe disease. The brunt of my thesis work was the focus of the Neuron paper, where we explored the role of GALC in the cellular pathogenesis of KD. I am currently applying to residencies in combined pediatrics and medical genetics.
I first met Dr. Feltri when she gave a talk at the local Neuroscience day at UB. She was a newly recruited PI, from the San Raffaele Institute in Milan, and was an expert in myelin biology and the development of the peripheral nervous system. Dr. Feltri, and her colleague Dr. Larry Wrabetz, were recruited to start a myelin institute at UB called the Hunter James Kelly Research Institute. The institute was developed to explore the underlying mechanisms of leukodystrophies, like Krabbe disease, as well as biological mechanisms in myelination and peripheral nerve development.
After one rotation in the lab, I knew I had found the perfect fit! She encouraged personal development and drive for a PhD student, while providing guidance and mentorship. She fosters a sense of passion and creativity in all of her PhD students and post-docs, and promoted an atmosphere of professionalism and comradery."
“After one rotation in the lab, I knew I had found the perfect fit!”
How do you find balancing your time in the lab with your work in the hospital (I see you are also studying for an MD!)?
"Since starting the program (over 8 years ago now!) I have been constantly flip-flopping between the lab and my clinical responsibilities. While adjusting between these environments has not been easy, it most assuredly has been rewarding. In fact, I think the two arenas complement each other nicely. The lab provides me with a creative outlet where I can pursue the mysteries of science and biology. Some of my greatest memories during my training are the thrills of discovery and the success of a challenging experiment. In the clinical setting, interacting with patients, and their families, is rewarding on a different level. Seeing families with debilitating medical conditions, and their appreciation for the services offered by the medical team, is deeply emotional and gratifying. It provides renewed energy for the drive to keep pushing forward. Of course, a loving and supporting family and group of friends also provides me with balance and comfort."
“Some of my greatest memories during my training are the thrills of discovery and the success of a challenging experiment.”
Can you provide me with an overview of the problems facing clinicians and scientists in treating and studying Globoid Cell Leukodystrophy (aka Krabbe disease)?
"Globoid cell leukodystrophy (GLD) is a rare demyelinating lysosomal storage disorder that affects infants and young children. The current treatment, hematopoietic stem cell therapy (HSCT), is only efficacious if delivered pre-symptomatically. The reason why this treatment is not curative, and why other therapies like enzyme replacement therapy have limited efficacy, is unknown. One major question the field (and other lysosomal storage diseases) faces, is why enzyme delivered peripherally to patients or animal models of disease is limited in its efficacy. Another major question concerns which cells require enzyme (GALC) and how HSCT provides its benefit."
"Our study revealed that GALC (the missing enzyme in GLD) is required independently by different cell types of the peripheral and central nervous system. Unexpectedly, we found that part of the disease process seems to occur when “cleaner cells” (macrophages) recruited to diseased tissues are unable to effectively clean up the damaged tissue. We think this may be part of the reason why HSCT (which provides donor macrophage precursors) is beneficial. Also surprising was that HSCT did not seem to work by correcting neighboring cells (a process called cross-correction). "
What part of this research did you enjoy the most? Did you ever have a Eureka moment when you realized your findings were special?
"I think that this project was the culmination of many small discoveries, which converged into the final story. I was perhaps most impressed when I saw that removing GALC in macrophages had a particularly severe effect in pathogenesis. I had eagerly encouraged Dr. Feltri to let me go down this path for quite some time, and she ultimately (somewhat) reluctantly agreed. I was glad that my hunch was right, and I could reassure her that exploring macrophages was, in fact, a worthwhile endeavor."
Was there anything in particular you struggled with? How did you overcome this, and what advice would you give other early-career scientists when encountering setbacks?
"I spent the first two years of my project cloning a complicated transgenic mouse model that ultimately did not work as expected. It was a major blow and was hard to move on from. I owe my resilience to my mentors, Laura and Larry, who encouraged me to keep pushing and reassured me that some experiments and projects will inevitably fail in the lab. The key (as I gathered from my PIs) is to be objective, resilient, and scientifically courageous."
How does this research impact the field of GLD research? Are you working on anything now in light of these findings?
"This work helps explain why HSCT is beneficial to patients with GLD, while also pointing out the limitations of the treatment. Many great scientists are currently working on new forms of gene therapy and modified HSCT for GLD and other lysosomal storage diseases. Dr. Feltri’s lab is continuing to work on exploring mechanisms of cross-correction of GALC, as well as Schwann cell specific mechanisms of GLD pathology."
"In 5 years, I will still be in training! Most likely I will be completing my residency/fellowship. Further down the road, I would like to work with patients with lysosomal storage diseases and pursue research related to therapy and a better understanding of such diseases."
A huge body of work like this cannot be completed on your own. Who would you like to thank for helping you publish it?
Drs. Feltri and Wrabetz were incredible mentors. They helped me every step of the way and guided me from day 1.
Dr. Daesung Shin, a co-PI, helped in developing the new GALC floxed mouse and was also involved every step of the way. He provided input throughout the project and taught me many of the laboratory and molecular techniques utilized in this study. Of course, a special thank you to all of the collaborators, who each provided an integral aspect needed for the success of this study."