Biophysicist in Profile

MADELINE SHEA

Growing up in the 1960s and 1970s made Madeline Shea more of a trailblazer than she had imagined as a young child playing with her “Handy Andy” toolkit and building primitive tables of sticks and twine. “I saw radical changes in the opportunities for female students by the time I was selecting a college,” she explained. “Most of the schools where I applied had just recently begun to admit women.” In fact, when she started her undergraduate career at the California Institute of Technology (Caltech), it was only the fourth class to admit women as undergraduates.

She was initially hesitant to major in biology, but she was drawn to the intersection of math, biology, physics, and chemistry. With her Bachelor of Science degree in chemistry almost completed, Shea took classes in genetics and developmental biology as a senior at Caltech, and found the study of living systems irresistible. “Living systems are non-ideal, nonlinear, and complex,” said Shea, “When I decided to go to graduate school, I applied to a wide variety of programs, in chemistry, genetics, physics, and biophysics.”

Shea found the best fit in the Thomas C. Jenkins Department of Biophysics on the Homewood campus of Johns Hopkins University, where in addition to rotating through labs oriented towards structural biology, she had the opportunity to meet faculty in a broad range of departments. Upon taking a physical biochemistry class cotaught by Gary K. Ackers and Lenny Brand, Shea became interested in Ackers’ work on transport theory and behavior of proteins. “I was intrigued by the questions he was addressing about allostery—how do subunit assembly, ligand binding and conformational change give rise to biological phenomena? How can we determine the populated states of a macromolecular complex and how do those govern biology?” Shea recalled. “It was music to my ears, so I asked if I could rotate in his laboratory.”

Moving from the Biophysics Department to the Biology Department, Shea began studying tobacco mosaic virus (TMV) coat protein assembly and then moved on to the bacteriophage lambda lysogenic-to-lytic growth switch. “It’s a paradigm for understanding developmental change and disease-induced disruption of networks,” Shea explained. “The ability to monitor individual sites in a multi-site DNA operator region using footprinting was akin to having a Maxwell’s demon telling us about occupancy at each site.” The work gave rise to her thesis work predicting the time-course of lysogeny and induction of lysis based on free energies and rate constants. The work also paved the way for a project on free energy coupling that provided a chance to derive analytical expressions (rooted in linkage theory) regarding the partitioning of free energy of cooperativity between sites. Bottom line: the weakest one is affected most.

Working in the Ackers lab as a graduate student and a postdoc, Shea met fellow postdoctoral researcher Michael Brenowitz. “Together with Don Senear and Ben Turner, we worked on the development of ‘quantitative DNase I footprinting’, a technique to resolve cooperativity in protein-DNA interactions,” said Brenowitz. “Madeline is perhaps the most direct, honest, and well-prepared researcher I have had the pleasure of working with.”

As a postdoc, Shea also had the advantage of an excellent scientific environment, according to James Lee, who was a visiting scientist in the Ackers lab during Shea’s postdoc. “Everyone in the lab was excited about their work, collegial, and most willing to share their knowledge,” said Lee. “Madeline played a major role in creating and maintaining that atmosphere and culture.” Another benefit of her time in the Ackers lab was that Gary was also an enthusiastic leader in the Biophysical Society. “He was generous about taking us to the Annual Meeting to present our work,” said Shea, “and I became hooked on biophysics and the Society, where I later served on Council and chaired the Membership Committee.”

During one of these Annual Meetings in the mid-1980s, Shea met Bertrand Garcia-Moreno, who was interested in Shea’s statistical thermodynamic modeling of the right and left operators of bacteriophage lambda. “It was truly pioneering research, way ahead of its time,” said Garcia-Moreno. “It marked in many ways the beginning of systems biology.” After a tour of the posters from Shea and others in the group, Garcia-Moreno pursued postdoctoral work in the same lab. Although they never formally collaborated, their projects mirrored each other, with Shea studying Ca2+- protein interactions and Garcia-Moreno studying H+- protein interactions.

Shea still has an effect on Garcia-Moreno today, though they no longer work together. Now the chair of Johns Hopkins University’s Jenkins Department of Biophysics, Garcia-Moreno works in the same building that holds bound copies of every thesis written by the graduate student in the department. “When graduate students in my lab begin to get itchy to leave the nest before they are ready, I instruct them to find and read Madeline’s PhD thesis,” explained Garcia-Moreno. “They usually come back to my office laughing—Madeline’s thesis was so extensive, so rich in data and chapters, that it had to be bound in two volumes, each one thicker than the next thickest thesis on the shelves.”

Today, Shea is a professor of biochemistry in the Carver College of Medicine at the University of Iowa. Her laboratory’s major projects are in two areas—calcium-mediated control of voltage-dependent sodium channels (funded by NIH) and regulation of calcineurin (funded by AHA).

In addition to teaching biochemistry to undergraduate, graduate, medical, and professional students, her department sponsors an undergraduate major, and Shea personally mentors many undergraduate students in her group. Five years ago, she founded the University of Iowa’s Fostering Undergraduate Talent—Uniting Research and Education (FUTURE) in Biomedicine program. The group sponsors faculty members from primarily undergraduate institutions to bring a student and work in a lab at the Carver College of Medicine over the summer. (For more details about the program, visit www.medicine.uiowa.edu/FutureBiomedicine.) Adrian Elcock, a colleague of Shea’s at the University of Iowa describes her as an excellent mentor to students and younger faculty members. “She has also been an outstanding leader in developing ties with other educational institutions in Iowa,” said Elcock. “In doing so, she has positively impacted the scientific careers of students and faculty well beyond the boundaries of our university.”

Down the road, Shea hopes to encourage young scientists to join the field of biothermodynamics. “This is one of the reasons I have been very active in the Gibbs Society of Biological Thermodynamics,” said Shea. The annual conference is unusual because trainees typically outnumber principal investigators two to one. Shea met Patricia Clark at a Gibbs meeting, and though the two do not work on similar biological problems, Clark has found Shea to be a fantastically supportive colleague. “One need only spend a little time talking with Madeline before it becomes clear that she loves thermodynamics and takes very seriously her responsibility to train a new generation of biophysicists,” said Clark. “I count myself lucky to be among those who have benefited from the seriousness with which she takes these responsibilities.”

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