Pediatric rheumatologist Elizabeth Mellins dies at 72

Elizabeth “Betsy” Mellins, MD, professor of pediatrics at the Stanford School of Medicine, died March 24. She was 72.

Mellins was a pediatric rheumatologist and immunologist whose laboratory made important discoveries about childhood inflammatory diseases. She was also a dedicated advocate for her specialty, a founder of one of its largest research networks, and a devoted and tenacious mentor to young scientists and physicians.

“Dr. Mellins was a consummate physician-scientist whose research acumen was driven by her deep compassion for children living with juvenile arthritis and other autoimmune diseases,” said Lloyd Minor, MD, dean of the Stanford School of Medicine and vice president for medical affairs at Stanford University. “Not only did she make important discoveries in her own lab, she worked tirelessly to expand research opportunities for everyone in her field, mentoring so many physicians to the ultimate benefit of young patients who can now access safer and more effective treatments for challenging chronic illnesses.”

Mellins tackled several difficult problems in immunology, focusing her research on a form of childhood arthritis, especially how immune markers known as MHC class II molecules function as inherited risk factors. Her recent work helped physicians understand an emerging, life-threatening lung complication of systemic juvenile idiopathic arthritis, or Still disease. Although it is not fully understood, scientists hypothesize that some newer drugs cause an immune-system imbalance in certain patients that leads to this complication. Mellins also gathered evidence for the autoimmune underpinnings of a severe pediatric psychiatric condition called pediatric acute-onset neuropsychiatric syndrome, or PANS. When her findings ran counter to perceived wisdom, she was adept at overcoming others’ skepticism.

“She was brilliant: She had the gift of not only knowing the science, but how to share it with the rest of the world,” said Jennifer Frankovich, MD, clinical professor of pediatrics and director of the Stanford PANS research program and the Immune Behavioral Health Clinic at Lucile Packard Children’s Hospital Stanford. “She wanted other people to care about the science as much as she cared, because it was science that would lead to better treatments for children.”

Having entered her profession at a time when female physician-scientists were rare, she worked hard to expand opportunities for young researchers, especially women.

“She loved finding and nurturing bright, interested young talent: undergrads, PhD students, postdocs, residents and fellows,” said Vivian Saper, MD, adjunct clinical professor of pediatrics. “Anybody who had gone through Betsy’s lab had a friend and mentor for life.”

‘Most likely to succeed’

Mellins was born Dec. 16, 1951, in Minneapolis, and grew up in Manhasset, New York, as the eldest child of an academically oriented family. Her father, Harry Mellins, MD, was a radiologist on the faculty of Harvard Medical School, and her mother, Judith Weiss Mellins, held a master’s degree in economics from Radcliffe College, which would later become part of Harvard. Mellins had two younger brothers, Bill and Tom.

After completing high school in 1969, Mellins earned an undergraduate degree from Cornell University in political science. While at Cornell, she enrolled for a summer quarter at Stanford and fell in love with it. She thought about becoming a teacher, but changed course.

“She had been voted ‘most likely to succeed’ in high school, and the best possible career path for a brilliant woman in 1969 was schoolteacher,” said her daughter, Lisa Mendelman.

Instead, Mellins did a post-baccalaureate year at MIT and went to Harvard Medical School, graduating in 1978. She then completed a pediatric residency at the University of Colorado Health Sciences Center in Denver, and a final year of residency and clinical fellowship in pediatric rheumatology at the University of Washington in Seattle, where she went on to a postdoctoral research fellowship in developmental biology.

While in medical school, Mellins spent a summer in the Sonoran Desert on the Tohono Oʼodham reservation in Sells, Arizona, gaining clinical experience. There, she met Paul Mendelman, MD, a physician in the U. S. Public Health Service. They were together for 48 years, marrying in 1980.

“Years later, she would say that if there had been mentors available, she would have been mentored to get a PhD, not an MD, based on her interests,” Lisa Mendelman said. “She was striking out into such unprecedented territory. It explains her lifelong commitment to scientific mentorship, to giving other generations experiences she did not have.”

Research focus

After completing her training, Mellins held faculty positions at the University of Washington and the University of Pennsylvania before being recruited to Stanford Medicine as an associate professor of pediatrics in 1996. In her laboratory, Mellins led studies of how different genetic variations of MHC II molecules contribute to a vulnerability to autoimmune disease. Her team investigated how immune cells called monocytes function in a variety of immune diseases, including Still disease, rheumatoid arthritis, psoriatic arthritis, asthma and PANS, seeking clues to disease pathogenesis and biomarkers.

Anybody who had gone through Betsy’s lab had a friend and mentor for life.

“Betsy had a relentless work ethic, always excited by new findings and developing the next question she wanted to solve,” said Mark Kay, MD, PhD, professor of pediatrics and of genetics. “She was a remarkable colleague in so many ways. Not only will I miss our scientific discussions but our friendship that included long talks about world events, music, art and our families.”

“She was the sort of person who would call and say, ‘Could we have coffee? I have this interesting idea and want to run it by you,’” said PJ Utz, MD, professor of medicine. “She was motivated by innate curiosity and a desire to discover.”

“Her North Star, within her research, was understanding the mechanism of disease and trying to look differently at the illnesses so you can cure them if possible,” Saper said.

One of Mellins’ most notable research findings, in collaboration with Saper, focused on drugs introduced in the early 2010s to block IL-1 and IL-6, molecules involved in the immune phenomenon known as “cytokine storm.” The drugs are used for Still disease, which is characterized by high fevers, joint inflammation and a risk of cytokine storm.

In 2013, reports emerged of mysterious, life-threatening lung problems in some Still patients, whose lungs showed unique changes in imaging and pathology. Mellins led detective work to demonstrate that children who experienced the problem had specific variants of certain MHC II genes. The discovery has enabled doctors to screen children for the genetic marker and use these drugs with caution in vulnerable children, monitoring them closely for early signs of the complication, or in some cases, avoiding giving the drugs to high-risk patients.

“It really changed the way we practice,” said Christy Sandborg, MD, professor emeritus of pediatrics, who was hired as clinical chief of pediatric rheumatology in 1997 and worked closely with Mellins.

Building a nascent field

In the late 1990s, soon after arriving at Stanford Medicine, Mellins recognized the need for a national research network in pediatric rheumatology and founded the Childhood Arthritis and Rheumatology Research Alliance (CARRA).

“Pediatric rheumatology at that period was very under-resourced, and it was impossible to do research on rare autoimmune diseases,” Sandborg said.

After attending an Arthritis Foundation special workshop on research in juvenile arthritis, Mellins was motivated to build a network that would offer funding and other resources for basic science in pediatric rheumatology and make it easier to conduct large, multicenter clinical trials. She began working with colleagues at Stanford and across the country on the project.

“Everyone in the field was so excited,” Sandborg said.

Among her contributions to the organization, Mellins wrote the first grant to the Arthritis Foundation for CARRA’s support and served as its first chairperson and head of the CARRA research grant committee.

“She recognized that you can do strong clinical work, but if you don’t do lab research, you don’t advance the field,” Sandborg said. “She contributed greatly to that over many years.”

CARRA is now a nonprofit organization with a membership of more than 400 pediatric rheumatologists and researchers across North America. It has garnered millions of dollars in funding and hosts a biorepository that scientists use for rheumatology research.

A devoted mentor

Mellins worked behind the scenes at Stanford Medicine to help recruit incoming medical students who wanted to pursue careers as physician-scientists, which she saw as an essential component of expanding the pipeline of medical researchers, Utz said. “She made a big difference in the recruitment and retention of women in our training programs, including the immunology PhD program and more recently the Berg Scholars Program,” he added.

Frankovich, who was mentored by Mellins early in her career, continued to rely on her advice as they studied PANS, an abrupt-onset, severe psychiatric condition that is thought to be secondary to post-infectious inflammation.

“Her advice was helpful because it wasn’t just about publishing a novel finding; it was about systematically deciphering a complex condition,” Frankovich said. “She was a realist: She knew that it would be very difficult and complex to prove that PANS was secondary to inflammation.”

She cared about the patients I was telling her about, the parents whose kids were affected and the researchers working on the disease.

One big obstacle to studying PANS was access to the parts of the brain involved — the investigators couldn’t biopsy affected brain regions, for example.

“Betsy said, ‘It will be more work to prove an immune hypothesis because we won’t have tissue,’” Frankovich said. “She helped me figure out the biological principles we needed to prove. And then she supported me all the way through each obstacle. When I came to her with a hypothesis, she would say, ‘We can do this, we can solve it,’ and then she would immediately dive into the next steps.

“All along the way she just cared: She cared about the patients I was telling her about, the parents whose kids were affected and the researchers working on the disease.”

Open doors

Mellins and her husband loved to host visitors from all over the world, their daughter said, including relatives from the United Kingdom and Israel.

“For a recent wedding anniversary, I made them an innkeeper’s book, an album of notes and pictures from the many people who have stayed with them,” Mendelman said. “She deeply valued human connection and she was so gifted at it; she would connect, and stay connected, with anyone.”

Riding his bicycle past Mellins’ and Mendelman’s home on the Stanford campus, Utz could always tell when they had their grown children, grandchildren or other relatives or friends visiting. “There would be five or six cars parked outside,” he said, chuckling.

Mellins and her husband loved live events, attending theater, sports, jazz concerts and modern dance with equal gusto. They didn’t have a TV; instead, “They went to endless performances all over the Bay Area,” Lisa Mendelman said. “Her vision of a balanced life included all of these humanistic things.”

Mellins also loved to read and stayed up to date on contemporary art and literature, deriving great pleasure from finding exactly the right book to give a friend or colleague.

“She drove all the way to my house to give me a copy of the brand-new, hot-off-the-press pediatric rheumatology book,” Frankovich said, adding, “I thought, ‘How did you know this was the book I wanted?’”

Mellins is survived by her husband, Paul Mendelman; son, Jeff Mendelman; daughter, Lisa Mendelman (David Jack); stepson, Adam Mendelson (Catherine Wallis); grandchildren, Oscar and Aila Mendelman Jack; brother Tom Mellins (Judy Weinstein); and nephew, Sam Mellins. 

Donations in her honor can be made to a designated fund at the Lucile Packard Foundation for Children’s Health: https://my.supportlpch.org/Mellins.