Dr. Maria Lehtinen
Associate Professor Harvard Medical School
Postdoctoral Fellow Harvard Medical School
Postdoctoral Fellow Folkhälsan Institute of Genetics
Ph.D. in Neuroscience Harvard University
Dr. Maria Lehtinen’s first experience in a research lab was not exactly a glamorous one. As a freshman neuroscience major at UPenn, eager for research experience but unqualified for nearly everything, Maria landed a volunteer position pipetting urine samples for a neuroendocrine project in a translational neuroscience lab. While she was fascinated with neurology, Maria’s primary motivation for volunteering in a lab was to boost her eventual application to medical school. It’s possible that she would have followed through with her medical aspirations had it not been for a bit of serendipity. Maria’s labmate suddenly quit, and Maria was asked if she could help fill the gap by sectioning brain samples and analyzing them for neurotransmitter levels. From that first moment working with a brain, Maria’s love for basic science research only grew. Today, she is an Associate Professor at Harvard Medical School. Her lab at Boston Children’s Hospital – where she holds the Hannah C. Kinney, MD Chair in Pediatric Pathology Research – is answering ground-breaking questions about the cerebrospinal fluid that bathes the brain.
While turning away from her long-standing plans for medical school was a difficult decision, Maria could not deny her growing sense during her undergraduate years that she should be a researcher rather than a physician. She followed that gut feeling to the neurobiology PhD program at Harvard University, where she planned to study neural circuits. However, following the graduate program’s recommendation to experience a variety of subfields, Maria chose to do one of her rotations in the newly established lab of Dr. Azad Bonni. The Bonni lab was investigating the cellular and molecular mechanisms of cell death and survival. As she dove into learning molecular techniques, Maria became fascinated by the questions the lab was pursuing. She decided to forgo her electrophysiology dreams and joined the Bonni lab. As when she had let go of her med school plans, Maria allowed her interests to drive her path forward rather than sticking to her preconceived notions of the future. Her open-mindedness and flexibility were crucial qualities as she hit the rough patches inherent in the journey towards a PhD.
Maria’s dissertation was ultimately quite different from the first projects she took on as a graduate student. “You have to throw a lot of things at the wall and see what sticks,” Maria says. “Science does and should involve a lot of failures.” As project after project stalled, Maria found motivation in her love for problem solving and her continued excitement for new questions and new directions. Ultimately, she focused on the role of oxidative stress in regulating neuronal survival using the cerebellar granule cell as a model. She discovered that cellular oxidative stress causes MST1, a protein kinase, to directly activate FOXO transcription factors, leading to cell death. After characterizing the MST-FOXO signaling pathway in mammalian neurons, Maria wondered whether the pathway had been conserved throughout evolution. She collaborated with Dr. Keith Blackwell’s lab to answer this question using C. elegans. The Blackwell group soon became Maria’s “lab away from lab” as she learned how to test her ideas in a new model organism. She discovered that MST-FOXO signaling does indeed modulate lifespan in C. elegans: the signaling mechanisms were well-conserved. In time, the other projects that Maria had started in her earlier years came to fruition too, either contributing to labmates’ projects or as her own side stories. One of them – an inquiry into the molecular mechanisms underlying a particular type of epilepsy – helped launch her first postdoctoral position.
During her PhD, Maria had become interested in the role of the cystatin B protein in a common form of epilepsy known as EPM1. Patients with EPM1 have mutations in the gene coding for cystatin B, and Maria hypothesized that the mechanisms underlying neurodegeneration in EPM1 might be related to oxidative stress. To pursue this question, Maria joined the lab of Dr. Anna-Elina Lehesjoki at the Folkhälsan Institute of Genetics in Helsinki, Finland. It was a perfect fit scientifically, as Anna-Elina had a cystatin B knockout mouse line. But the lab’s location was also important. Maria is originally from Finland, and this position meant that she could be closer to family and friends, with the added benefit of being able to travel in Europe more easily. Maria had thrown herself into work as a graduate student, leaving little time for life outside the lab. While she had loved the work she was doing, when it came time to choose a first postdoc, Maria knew that she wanted to find a healthier work-life balance. Unsurprisingly, she still excelled at the work aspect of that balance, ultimately showing that cystatin B deficiency sensitizes neurons to oxidative stress, leading to increased cell death and neurodegeneration.
As she began to consider how to launch her independent career in research, Maria decided to return to Boston for a second postdoctoral fellowship with Dr. Christopher Walsh. She wanted to learn the basic mechanisms of brain development and genetics so that she could combine this knowledge with her previous experiences to design better therapeutic interventions for neurologic diseases. Towards the beginning of her time in the Walsh lab, Maria had an aha moment that would ultimately guide her work as an independent investigator. She and Chris were looking at coronal sections of the developing brain, trying to map out a direction for her project. As they marveled at how much real estate the cerebrospinal fluid (CSF) occupies during development, she noticed that the cortical neural progenitor cells that lined up along the ventricles were extending their processes into the CSF. She knew at that moment that this cell-CSF interaction must be important. Maria ultimately found that CSF has an age-dependent effect on proliferation of neural progenitors. After finishing her postdoc, Maria started her own laboratory at Boston Children’s Hospital to dive more deeply into understanding CSF signaling in the brain.
Studies of brain development had shown that there are several health- and growth-promoting factors transiently present in the CSF, likely produced by the choroid plexus – a structure located in the ventricles that produces CSF. Maria’s first goal in her new lab was to discover where and how these factors were produced. She thought these would be relatively easy questions to answer, but she was quickly humbled by the unique technical challenges of studying a floating structure deep within the brain while it is producing a fluid that gets turned over multiple times a day. Challenges, however, can often mean more rewarding results. In the years since, the Lehtinen lab has begun to take on fundamental questions about the choroid plexus, its cellular heterogeneity, and its distinct properties and roles in the different brain ventricles. Maria works with collaborators to bring a wide range of new technologies to these questions, from single-cell RNA sequencing to live cell imaging deep within the brain.
In addition to facing the complexities of studying the choroid plexus, Maria also found a different type of challenge when she started her lab: it was a bit lonely. Her experience of science thus far had been a social one, working side-by-side with labmates and striking up spontaneous conversations about science or life outside the lab. But as a new faculty member, she often found herself alone in her office. Her trainees came to discuss their science, of course, but they were not really stopping by to chit-chat as a friend might. Eventually, Maria found ways to combat the loneliness by serving on various committees and forming friendships with other faculty members. She also poured her attention into mentorship, strengthening her connections with her trainees – connections that are of the utmost importance to her.
Maria believes that the mentor-mentee relationship is critical and begins with honest communication. “If there is a common understanding of what everyone’s goals are and what we hope to achieve, that’s step number one to a good mentor-mentee relationship,” Maria says. She looks back on her own experience in grad school as she tries to help her trainees through their time in her lab. Maria admits how difficult it can be to know how to shape a project by combining preliminary data with the literature, while pragmatically assessing the lab’s resources and technological limitations. She knows from experience that this skill is often learned through trial and error – that facing adversity, while frustrating, can become a strength. Maria encourages her students and all young scientists to persevere, to stay open-minded, and to keep looking outside the box. “Talk to people! Don’t stay in your bay. You’ll eventually make those connections that will help everything move forward.” Indeed, Maria’s own open-mindedness, ingenuity, and dedication to mentorship and collaboration is inspiring a generation of scientists to tackle the mysteries of CSF signaling in health and disease.
Check out Catie’s full interview with Maria on January 29th, 2021 below or wherever you get your podcasts!
