Meet a Whitehead Postdoc: Michael Gallagher

Michael Gallagher is a postdoc working jointly in the labs of Whitehead Institute Founding Member Rudolf Jaenisch and Whitehead Institute Member Richard Young investigating gene regulation in neurodegenerative diseases. His work is currently funded by a fellowship from the National Institute on Aging. We sat down with Gallagher to learn more about him and his experiences in and out of the lab.

What do you investigate?

I’m investigating gene regulation in different brain cell types in the context of neurodegenerative disease. Neurodegenerative diseases like Alzheimer’s, Parkinson’s, and frontotemporal dementia have become a global health crisis. Their prevalence in the US is skyrocketing, and in spite of all of the clinical trials over the past few decades dedicated to finding effective therapies, there’s still very little we can do to treat them. One thing I found interesting is the growing evidence that many of the mutations that predispose someone to these diseases are not in the genes themselves, but in genomic regions such as enhancers that regulate the expression of other genes. So, in order to understand the risk factors and the pathways involved in these diseases, you have to know where the active regulatory regions are in all of the brain cell types—and it does differ drastically between cell types. Those data for the most part don’t exist, so I’m trying to build a database of where the enhancers are in each cell type, as well as which genes they regulate, which I think will be very useful for geneticists and neurologists. Equally important is the fact that these data will help us understand how the cells we make in lab compare to those in the human brain, which we hope will allow us to fine-tune gene expression in our cells to make them more physiologically relevant.

What are the steps to investigate these research questions?

The first step is to use human stem cells to generate all of the major brain cell types, which I’m doing in Rudolf’s lab. Then I’ll perform genome-wide assays developed in the Young lab, as well as by Whitehead Fellow Olivia Corradin, to find out where all of the active enhancers are in each cell type. Once we have that information, I want to look for overlap of known mutations associated with neurological diseases with these enhancers. Then we can test the most promising ones to see which genes they regulate, which cell type the effect is coming from, and how they are contributing to disease risk. One complication is that we expect to see significant differences in gene expression between the cells I make and actual human brain cells, based on previous research. I’m going to try to reduce those differences using approaches such as epigenome editing, so that our cells better match true human brain cells, and thus may serve as better models for human disease.

How did you end up working in two labs? What is that like?

The project I’m working on is challenging. It requires being able to generate all of the brain cell types, which very few labs other than Rudolf’s can do, and using certain genomics assays, which very few labs other than Rick’s can do. It’s exceptionally rare to find a collaboration that allows you to do both. From what I understand, the Whitehead Institute philosophy is that whatever is the most effective way of getting the science done is the way it should be done. The goal is to remove barriers to good science, so if you are interested in doing a joint mentorship, and if you and the PIs can come to an agreement, it's pretty open ended how you use the two labs to accomplish that goal. So far I've spent almost all of my time in Rudolf's lab because what I've been doing is using human stem cells to produce different brain cell types, some of which take three months of just waiting. I’ve started to collect DNA and RNA from these cells and then do these genome-wide assays that Rick's lab has a lot of expertise in, so the actual assays I'll be using as the end point to generate data will be coming from Rick's lab, as well as Olivia Corradin’s lab, who is a key collaborator. I would say I’ve been spending 90% of my time in Rudolf’s lab, but I expect that to change, especially since I have a second project now that is more 50-50 in terms of which lab has the approaches I need. I am benefitting a lot from both labs. They each have different strengths and personalities, and attending both lab meetings is really helpful for me because I get feedback from people with very different backgrounds and thinking styles.

What did you want to be as a kid?

I didn’t have too many specific ambitions, but probably around third grade I would have said baseball player. I was really into baseball. I was a good baseball player, and I kind of idolized my heroes. My parents both grew up in Long Island where the Mets are big so I became a Mets fan because of them.

Do you collect anything?

When I was a kid I had like 30,000 baseball cards. Now I don’t collect anything. I’m kind of a minimalist at home.

What’s the biggest disaster you’ve ever had in the lab?

During my PhD, when CRISPR came out, my thesis advisor and I decided that we had to edit this regulatory region we were studying to prove my thesis. I spent the better part of a year doing that and then got a completely negative result that suggested that the region wasn't even functional. We realized the problem might have been that we did the experiment in a cell type that has no real relevance to the process we were studying. We had used the cell type because it was what everyone was using for gene editing, and it was known to work, but in the meantime I had learned how specific these gene regulatory elements can be to different cell types. I spent another nine months trying again with what we thought was a more relevant cell type, and ended up with a result that might have supported our thinking but was inconclusive. So after almost two years of intense work, we didn’t learn anything. To spend so much time doing something as powerful as gene editing, which was new and exciting, and to spend all that time slaving away with 500 clones that I had to maintain and screening all of them, only to get a negative result felt like being punched in the stomach by a heavyweight. I was crushed, and it took me a few weeks before I was no longer depressed on a daily basis. 

What’s the biggest surprise you’ve ever had in the lab?

The biggest shock to the system for me was when I first started doing research in the lab that would become my thesis lab. I had never done a true independent research stint before. I did my first experiment, trying to replicate what someone else had shown, and the data were bad. It was noisy, it was uninterpretable, it didn't look the same. I thought this was a big failure, and I didn't like it. Thankfully I had an understanding thesis advisor who really cared about the people who worked for her and helping them grow as scientists. I had to learn that as a scientist, ninety percent of what you do will not work, and anything you do that you think works, you may find out a day later or ten years later that it was wrong. I came to realize that failure was the norm, but doing that requires a significant change in mindset from what most people have in college, or in many non-scientific fields. It was tough in the beginning; there are no textbooks on this, and people don't tell you about it. You just have to get experience and learn.

What are your hobbies outside of work?

For many years, I was really into exercise and working out, but unfortunately in my mid to late twenties I had a bunch of injuries that made it really hard to keep doing it. Also, with the amount of time I spend working as a postdoc, it’s not feasible to spend lots of time at the gym every day like I used to. I still go running on weekends. My other big hobby is playing guitar and writing songs. I’ve been doing that consistently since I was fourteen, learning how to play the songs of my favorite artists and writing original stuff. At first, I was more of a guitar aficionado, but I have found that I also really enjoy songwriting.

What kinds of songs do you write?

My main influences as a songwriter are acoustic rock bands that were around in the mid ’90s to early 2000s, like Dave Matthews Band, Counting Crows, John Mayer, Vertical Horizon, things like that. That’s what I was listening to when I started writing songs.

Where do you see yourself in ten years?

I want to be a tenure-track principal investigator (PI), running my own lab in some sort of academic environment. It’s hard for me to imagine doing anything else. I could see myself in either a university or a nonprofit like Whitehead Institute, but definitely a place where you have academic freedom to work on what you want, and to apply for grants, and you have grad students and postdocs in your lab.