August 2020: Wichterle Lab
What is the main focus of your lab?
We use mouse and human pluripotent stem cells to study neuronal development, neuronal maturation, and to model neurodegenerative diseases.
How long have you had your lab? When did you join Columbia University?
I joined Columbia University as a postdoc in 2000 and started my own lab in 2004.
How big is your lab currently?
Where is your lab located?
Our main lab is located in P&S 14-401, ALS Therapeutics Core is located in the Motor Neuron Center on the 3rd and 4th floors of the P&S building.
What are the most exciting projects/directions in the lab at this moment?
On the basic neurodevelopmental front, we discovered that neuronal genes are controlled by a uniquely complex system of regulatory elements, located in expanded non-coding genomic regions. We also found highly dynamic patterns of gene expression in postnatal motor neurons, indicating that motor neurons undergo a complex, transcriptionally regulated process of maturation. We are studying what makes our nervous system different from that of other vertebrates. We started to map molecular mechanisms that control different rates of neuronal development and neurogenesis in mouse and human.
In collaboration with Brent Stockwell’s lab at the main campus, we developed a new small molecule kinase inhibitor that protects motor neurons from the toxicity associated with accumulation of misfolded proteins, a common problem in many neurodegenerative diseases. This new MAP4K inhibitor has high potency, stability, is orally bioavailable, and readily crosses the blood brain barrier. Jointly with the Project ALS foundation and Therapeutics Core at the Motor Neuron Center, we are running pre-IND studies, in hopes of entering clinical trials in near future.
What are the model systems that your lab is using?
We use primarily mouse and human stem cell lines engineered to facilitate our basic and translational studies. We have developed a series of cell lines that carry motor neuron reporter genes, cell lines with doxycycline inducible transcription factors used to study transcriptional control of motor neuron genes and for motor neuron reprograming. Most recently we developed a series of cell lines that carry inducible forms of Cas9, CRISPRa and CRISPRi that we are utilizing in genetic screens for modulators of motor neuron differentiation and motor neuron survival.
What are the key techniques that your lab is using?
We perform stem cell engineering, chromatin immunoprecipitations, genomic analysis, single cell analysis, cell culture, genetic and small molecule screening, high content imaging, neuronal survival assays, in vivo AAV-PHP.eB based genetic manipulations, spinal cord histology, and mouse motor behavior studies.
What facilities or equipment does your absolutely lab rely upon?
We use regularly the FACS facility and have a long standing collaboration with the Stem Cell Core facility. Beyond the CSCI, we use imaging facilities, animal facilities, and genomic facilities in the Cancer Center.
Who shall be contacted with questions about equipment, resources and training?
Feel free to contact me, Hynek Wichterle.
What's your best approach to mentoring trainees in the lab?
That’s very individual, as everyone has different strengths. Overall, I view my primary role as an adviser, facilitator, and a nudger. My expectations are that graduate students and postdocs are smart, motivated, and independent. I try not to be heavy handed. I prefer to discuss projects, go over raw data, brainstorm unanticipated results, and help to steer projects through the rocks and crevasses of the daily science.
Who were your most influential mentors/role models in science and what did you learn from them?
I was fortunate enough to work with two fantastic mentors with very different styles. Arturo Alvarez-Buylla at the Rockefeller University taught me that science should be exciting and bold and Tom Jessell taught me that one needs to dig deep to find true gems.
What would be your career advice for students/postdocs?
Do what you love to do, do it hard, do it honestly, and be kind. Do not get fixated on specific career goals, be open-minded about opportunities that you find along the way. Most importantly, you should seek thrill, not satisfaction in science. Satisfaction is when experiments confirm your ideas, thrill is when they prove you wrong.
Are you accepting rotating students at the moment?
How do members of your lab celebrate accomplishments?
Low concentration ethanol (after 5).
Does your lab have any fun traditions?
Annual ski trip to Hunter (before global warming) and more recently a weekend in boonies
What is the key to running a successful lab?
I wish I knew… Getting the right people.