Recent PhD graduate student Joe Lalli has had a fascinating journey on his way to the Cellular and Molecular Biology program and the MD/PhD program at UW-Madison. Lalli started as a self-proclaimed “4th grade nerd” amateur coder and grew to a junior highschooler interested in politics. While remaining active in political campaigns in high school, Lalli decided to shift his focus to biomedical research.
“The MD/PhD track seemed like a good way to marry my interest in working with people and working on long term, curiosity-driven projects,” he says.
Lalli had been working in a virology lab for several years before the COVID-19 pandemic hit. He found himself switching to a different path after discovering a passion for psychiatry during his clinical rotations. His early coding experience helped him specialize in bioinformatics. Eventually he found the Werling Lab where he has been able to combine his neuropsychiatric interests and hone his bioinformatics skills, both of which allowed him to publish a paper and present the work to national genomics committees.
“I would never have planned this,” Lalli says. “But I enjoyed almost every step.”
Joe shared some insights from his time in the PhD program.
What are the main goals of your research, and what technologies do you focus on?
The most commonly used human genome (hg38) is only 92% complete. The remaining 8% of it is highly variable, repetitive, and difficult to sequence. Recent advances in genetic sequencing technology have allowed researchers to fill in these gaps, and additionally document the common ways in which peoples’ genomes structurally differ from the reference genome. My research is focused on examining how including these new regions improves the accuracy of existing computational genetics methods.
The dataset I work with the most is called BrainVar2 – it’s a collection of genetic data obtained from the brains of fetuses, children, and adults from six weeks post conception to 90 years old. These data are from individuals of diverse ancestries, and my PI Dr. Donna Werling’s lab is focused on understanding sex differences in neurodevelopment. Our data are all ‘short read’ sequencing. Structural differences between individuals’ genomes are common, commonly associated with changes in neurodevelopment, and are difficult to measure using short read data. Use of complete genomes and pangenomes makes identifying these differences much easier.
What are the big-picture questions and significance of this work?
Broadly speaking, I’m trying to demonstrate that including these regions in of our analyses improves the accuracy of all genetics research. Repetitive, variable regions of the genome are 1) evolutionary younger, and thus more likely to be responsible for human-specific traits, and 2) are often involved the in the development of neuropsychiatric copy number variant disorders. Thus, these regions matter a great deal – especially for researchers interested in neurodevelopment and neuropsychiatric disorders.
What is the single person, event, or experience that most influenced your trajectory to where you are today?
I think that my “trajectory” felt most fragile during COVID, after I had left my previous lab. I was dealing with some personal struggles at the time, and at a low point. That was when Dr. Donna Werling agreed to take me into her lab. “Find a PI who is a good fit” is a cliché at this point, but I didn’t realize that what constitutes a good fit can change over time. Dr. Werling helped me get off my feet. She was patient and supportive when I most needed it. I wouldn’t be here today if it weren’t for her.
What advice would you have for a young person interested in graduate school or research?
PhDs are hard because you do not have any external measure of success. It is easy to spend weeks doing work that ends up being useless. During the low points of my PhD, I withdrew from the world and felt worthless and unseen. During the high points, I felt like I was getting a stipend to play with data every day. So get hands on experience now, ideally with someone who is willing to let you try out your own ideas. Does the work feel like drudgery? Or does it feel like play? Do not go into this career unless you can find some way to enjoy it for its own sake, because success is rare and often only clear in hindsight.
Lalli is also part of a curling league and competes with a team in Arlington, WI as the team’s third. He will be applying to psychiatry residencies in the fall and hopes to be able to continue his research.
“I want to split my time between leading a team that combs through these new regions of the genome for clues to understanding psychiatric illness, and working with patients who remind me why the work matters.”