December 2021: Baldwin Lab

Background:

What is the main focus of your lab?

We apply reprogramming and stem cell based methods to try to solve some of the critically important, yet difficult, problems posed by the recent explosion of genomic sequence information. We explore genome diversity and its cause and consequence at three levels: at the individual cell, between humans as it relates to disease and between species using interspecies chimeras. A main focus of the lab is to generate the most useful cellular and genetic models for human risk for neurologic and vascular disease. To do this we apply reprogramming, human iPSCs and more recently high content long-term time-lapse imaging.

How long have you had your lab? When did you join Columbia University?

My lab moved to Columbia from Scripps Research in mid-2020. I was a Professor at Scripps and UCSD for 14 years in the Cell Biology and Neuroscience Departments. Before that I was a post doc at CUIMC with Richard Axel and my lab returned to the exact space where I did my postdoctoral research while awaiting our renovation of our current home on the 14th floor of Hammer Health Sciences Building.

How big is your lab currently?

My lab typically ranges from 10-16 people with a mix of PhD students, post docs, technicians, masters students and undergraduates. Currently the lab includes 5 post docs, one PhD student, two PhD rotation students, a masters student and a technician. We are actively recruiting new members and welcoming new PhD and MD/PhD students for rotations.

Where is your lab located?

14th floor of Hammer Health Sciences Building. We have excellent views to the north and south.

Current affairs:

What are the most exciting projects/directions in the lab at this moment?

1. Defining a transcriptional periodic table of the brain using reprogramming. We have built a large library of human transcription factors (TFs) to show that screening TFs in an unbiased combinatorial way can identify new pathways to produce human neuronal subtypes of high biologic interest. We are now applying this combinatorial library approach to better understand brain disease, development and evolution. This project builds on our recent Nature paper (Tsunemoto et al. Nature 2018) and is funded by an NIH Pioneer Award.
2. Demystifying the most expensive and impactful genetic risk locus for cardiovascular disease using genome editing and iPSC-derived vascular cell models. This research area builds on work published in Cell in late 2018 (LoSardo et al) linking human genetic diversity to disease. We found that the 9p21.3 locus, which is responsible for 13% of coronary artery disease (CAD) and present in 75% of most worldwide populations, leads to dysregulation and altered splicing of a lncRNA ANRIL. This toxic ANRIL isoform affects cell features linked to CAD and arterial plaque formation through a newly defined gene network of ~3000 genes, including more than 1/3 of known other CAD risk genes. Current projects are to develop methods to modulate the toxic ANRIL and examining the cellular, transcriptomic and epigenetic effects of the risk loci on cell type diversity in the vasculature.   
3. Interspecies brain chimeras: Genomic differences between species afford them their unique behaviors, sizes, lifespans and disease susceptibilities. To ask which of these attributes are encoded within a particular cell vs. those that depend on the overall environment, we have begun constructing interspecies blastocyst chimeras that allow us to generate animals in which mouse hosts with disabled neuronal cell types (i.e. olfactory sensory neurons) are tested for the capacity of rat neurons to functionally complement the neurons at the anatomic, synaptic and behavioral level. Future work aims to expand interspecies brain chimeras to more evolutionarily distant species. 
4. Single cell somatic mutation in development and disease: Our lab pioneered the use of cloning and reprogramming to amplify and sequence the genomes of individual somatic cells including post mitotic neurons, uncovering striking diversity among the genomes of your brain and body. We, and other groups, are now discovering unexpected variation in the source, rate and potential consequence of mutations that arise after fertilization during development and aging. We are now expanding our studies of individual neuronal (and other cell type) genomes to produce a history of genomic threats and DNA repair across different somatic cell lineages. We also wish to and identify consequences of these mutations in development and aging of the brain, vasculature and germline.

What are the biggest accomplishments that your lab recently had?

Moving our lab twice during the pandemic.

Technology:

What are the model systems that your lab is using? 

Human cells produced from iPSCs or through direct reprogramming, mouse and rat genetic models and a new project where we build interspecies chimeras by injecting pluripotent stem cells from one species into the embryo of another. We are expanding the types of models we use as the stable of different animal iPSCs grows.

What are the key techniques that your lab is using? Are you open to training scientists from other labs?

We have a long history of expertise in reprogramming, cloning and directed differentiation of cells through transcription factors, lentiviral library screening and generation of chimeric animals (mice cloned from neurons, mice entirely from iPSCs, interspecies brain chimeras). We also recently acquired an AI-based high content long-term time-lapse imaging microscope that will allow us to sensitively identify the cellular and morphologic changes that differ between cells affected by human disease risk genes by tracking and imaging the same cells over periods of weeks or months.

What facilities or equipment does your lab absolutely rely upon? Do you use CSCI cores?

We are very grateful to the CSCI cores which we have used for FACS, qRT-PCR and help getting our iPSC facility up and running. We are now working with the core to establish a method for generating vascular cells in vitro.

Who shall be contacted with questions about equipment, resources and training?

Dr. Baldwin or Tyler Buckley

Training:

What's your best approach to mentoring trainees in the lab?

My lab is highly collaborative and I focus on helping trainees work on teams within the lab and also gain exposure to other labs and their PIs. Historically this has provided my trainees with a broad-based network and access to different training philosophies and technologic expertise. Within the lab I try to meet with each trainee once a week independently with quarterly re-calibrations of project goals and timelines. Now that we can be in the lab in person together I also enjoy informal interactions talking about data and looking at data.

Are you accepting rotating students at the moment?

Yes.

Lab management

How do members of your lab celebrate accomplishments?

My lab loves to celebrate accomplishments with food. We have enjoyed going out to dinner together exploring the wonderful and diverse restaurants in New York City. We have also had group potluck (or takeout) dinners in my apartment and are now adding some art and outdoor adventures as it becomes safe and feasible.

CSCI:

What was the main reason of you joining CSCI? What are the beneficial aspects of CSCI membership for your lab?

We have been extremely happy to be part of the CSCI community since we moved during the pandemic. The shared resources, trainee talks, invited lecturers and the retreat have helped the team integrate better into the very large biomedical community at CUIMC and Columbia and we are pursuing collaborations with several members already.

What do you plan to bring to the CSCI community?

We hope to bring our enthusiasm and long experience in pursuing interdisciplinary collaborative research and new technologies. We seek problems that are not only translationally important but also uncover new biologic concepts or mechanisms. For this reason, the broad range of labs, research areas and technologies that comprise the CSCI are a perfect fit for our lab and we plan to help further bolster the program and foster interactions whenever possible.