Dr. Malú Tansey
Professor, Indiana University
Postdoctoral Fellow Washington University in St. Louis
PhD University of Texas Southwestern Medical Center
Dr. Malú Tansey’s unique career journey has woven in and out of the academic sphere, leaving a lasting impact on the fields of neuroimmunology and neurodegenerative disease. Today she runs a lab at Indiana University School of Medicine, where she is a Professor of Neurology, the James A. Caplin, MD Chair in Alzheimer’s Research, and Director of Neuroimmunology Research at the Stark Neurosciences Research Institute. Her lab studies the interaction between the immune system and the brain, particularly in the context of neurodegenerative diseases like Alzheimer’s and Parkinson’s diseases.
There was a good dose of serendipity involved in Dr. Malú Tansey’s first foray into neuroscience. Although she loved biology in high school and majored in biology as an undergraduate at Stanford, Malú was not particularly drawn to studying the brain. Her PhD work at UT Southwestern focused not on neurons but on the molecular intricacies of muscle cells. Malú found that the enzyme calmodulin-dependent kinase II (CaMKII) modifies a second enzyme, myosin light chain kinase, ultimately increasing the threshold of activation needed for a muscle cell to contract. Thus, the interplay between these two enzymes helps to regulate the process of smooth muscle contraction.
After finishing her PhD, Malú began searching for postdoctoral opportunities in St. Louis because her husband had matched at Washington University in St. Louis for his medical residency. As she weighed her options, she prioritized finding a supportive mentor and a positive lab environment. To this day, she continues to encourage this approach to her mentees, arguing that the research topic doesn’t matter quite as much. “You’re not going to end up studying that for the rest of your life—it’s about learning to ask good questions.” Malú’s strategy for choosing a lab led her to accept a position working with Dr. John P. Merlie at the intersection of muscles and neurons. Muscles need acetylcholine receptors to receive motor commands from the nervous system, and a molecule called acetylcholine receptor-inducing activity (ARIA)—later renamed neuregulin—promotes expression of those receptors in the muscle cells. However, the molecular mechanisms underlying ARIA’s induction of acetylcholine receptor expression were unknown. Malú discovered that activation of two cellular signaling pathways (Ras/MAPK and PI3K) was required for ARIA’s effects on muscle cells.
After the untimely passing of Dr. Merlie, Malú continued her postdoctoral training in the lab of Dr. Eugene Johnson. This her first foray into the brain. Still retaining an interest in signaling pathways from her PhD, Malú set out to investigate pathways that confer resilience to dopaminergic neurons, which can be vulnerable in disease states. The lab was concentrating on the newly discovered GDNF family of trophic factors, molecules that support a cell’s growth and survival. These factors are secreted by glial cells and help maintain the health of nearby dopaminergic neurons. Malú focused on a trophic factor called neurturin, and she helped to identify and characterize its receptor and co-receptor on dopamine neurons, as well as the molecules that recruit the receptor to its proper place in the cell membrane.
As she wrapped up her postdoc, Malú wanted to move into the private sector. She joined a small biotech startup called Xencor and was put on a project with the goal of designing and validating new inhibitors of tumor necrosis factor (TNF), a pro-inflammatory factor widely involved in inflammation. The TNF inhibitors on the market would soon be off patent, so the search was on to find other inhibitors and patent new, better ways to treat chronic inflammation and related diseases. At first, Malú was not thrilled to be working in immunology, but she soon got swept up in the exhilaration of learning something new. She also came to value the team-based science inherent in industry. However, not having autonomy sometimes came at a price, and there was one meeting in which her supervisor shot down her idea for an experiment. After garnering the support of the company’s CSO, Malú stood up to her supervisor, expressing the importance of doing data-driven science in which “crazy” ideas are abandoned only if and when the data prove them wrong. This is an approach that has allowed Malú to do pioneering work throughout her career.
Ultimately, Malú’s team at Xencor was successful and, in 2003, they published their results in Science. The paper details the company’s efforts to use automated protein design software to create mutants of factors like TNF. They identified a mutant form of TNF that does not activate the TNF receptor and therefore does not have the same pro-inflammatory effects. However, TNF proteins typically hang out in groups of three (“trimers”), and Xencor’s mutant protein was close enough in structure to TNF that it could form trimers with endogenous TNF, effectively disabling it and reducing inflammation. Just over twenty years later—and after research from Malú and others has underscored the role of inflammation in neurodegeneration—their drug is now in phase II clinical trials for Alzheimer’s disease.
Despite the clear success of her work at Xencor, Malú desperately missed teaching and mentoring. In addition, she grew anxious about the unstable nature of industry—if a company changed its business plan, a whole group of people could be laid off even if they were excellent at their jobs. Thus, Malú decided to return to academia. While at Xencor, she had become intrigued by autopsy reports of activated immune cells in the brains of patients who had died from neurodegenerative diseases like Alzheimer’s and Parkinson’s. She asked the leadership at Xencor if she could use the TNF inhibitor they had created and test its efficacy in models of neuroinflammation. They agreed, and she brought this new tool with her as she started as an Assistant Professor back at UT Southwestern where she had earned her PhD.
While neuroinflammation is a hot topic today, in the early 2000s it was not so popular, and neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases were mostly considered to be unrelated to the immune system. This environment made it tough for Malú to secure research funding from the NIH, so it seemed like a godsend when the Michael J. Fox foundation put out a call for proposals studying neuroinflammation in Parkinson’s. Malú applied and received a grant, and her team set to work. They found that, remarkably, injecting Xencor’s TNF inhibitor into the substantia nigra reduced the death of dopaminergic neurons by about 50% in two very different mouse models of Parkinson’s disease. These results not only formed a launch point for the rest of Malú’s career, but they also served as validation of her hypotheses that inflammation played an important role in neurodegeneration—hypotheses that many of her colleagues had laughed off as inane or impossible.
Today, Malú’s lab still focuses on neuroinflammation and its role in Parkinson’s disease, but Malú has begun to look outside the brain for clues. She is a proponent of a hypothesis that a subset of Parkinson’s cases start outside the brain with peripheral inflammation, and the pathology then migrates to the brain and wreaks havoc. One of her current projects focuses on a gastrointestinal cell type called enteroendocrine cells, which express high levels of a protein called alpha-synuclein. Misfolded, aggregated alpha-synuclein is a hallmark of Parkinson’s disease, and Malú believes this pathology can sometimes start in the gut and move along the path of the vagus nerve to the central nervous system. If this is true, Malú imagines a future in which Parkinson’s disease risk might be identified via colonoscopy and treatments could be administered long before the nefarious misfolded proteins ever reach the brain. Malú is quick to give credit to the members of her team who thought outside the box (in this case, outside the brain) and brought these ideas to her. “It’s always the ideas that get bounced around in the group that lead you to the next frontier,” she says.
As she heads out into her newest frontier, Malú admits that she has faced and continues to face the struggles that come with being a woman of color in academia. Not even her decades of experience or her myriad honors and promotions can protect against the microaggressions and social norms that attempt to suppress her voice and the voices of others like her. However, Malú has found ways to effect change. For instance, when she is invited to speak at a meeting, she asks to see the list of other speakers. If there is a glaring gender imbalance or lack of diversity, she will make her participation contingent on fixing these inequities. Malú also advises women—who tend to air on the side of being polite in meetings, on committees, etc.—not to wait to be called on but instead to proudly and assertively speak their ideas whenever there is an opportunity to do so. Malú’s own courage to propose and pursue innovative ideas has had an immeasurable impact on the field of neuroimmunology.
Find out more about Malú and her lab’s research here.
Listen to Nancy’s full interview with Malú on December 30, 2024 below!
