BBI Faculty Conversations. BBI member Dr. Sarah Baxter MD, PhD, is an Acting Assistant Professor in the Department of Pediatrics at UW, and Attending Physician in Pediatric Rheumatology at Seattle Children’s Hospital.
BBI: What is the focus of your work? How does it relate to BBI’s focus on precision medicine?
Dr. Baxter: I study severe immunological illnesses in children, the same children whom I treat. Of course, I’m biased, but to me, the immunological illnesses of my pediatric patients are at the very heart of precision medicine. Over the past several years, rheumatology has developed brilliant, targeted drugs (mostly small molecules and biologics) that can hit specific proteins or pathways to treat immunological illnesses. But we don’t know which patients to treat with which drugs. Either no treatment or mistreatment with the wrong drug can lead to harm to our patients. To enable us to treat each patient appropriately, we need precision medicine.
My BBI project focuses on one of the most complex of these immunological illnesses – systemic lupus erythematosus. Lupus is quite common in adults. It starts in childhood in 10 to 20 percent of patients. This childhood-onset lupus is typically more severe than the adult-onset disease. We don’t know what causes lupus, in adults or children. Our current thinking is that for each patient, some trigger, which could be genetic or environmental or both, leads to a loss of immune tolerance. This loss of tolerance then spreads, and months or years later the patient presents with devastating multisystem disease.
As rheumatologists, we then treat this multisystem disease, without knowing the original trigger or driving force. Our field has precision treatments, but we do not know which ones to use for which patients. There is a fundamental disconnect between the very specific tools that are available to us therapeutically, and the lack of information about the fundamental causes of lupus in the individual patient that would enable us to use the correct tool. I want to change that.
BBI: Where does the research stand? How have you approached the disease and the genetics of the disease recently?
Dr. Baxter: My field is only beginning to understand the genetic causes of lupus. I want to build on this knowledge for the direct benefit of my patients. That is my BBI project. My mentor is Mary-Claire King, a world-renowned geneticist whom I’ve known since I entered the UW MD/PhD program 15 years ago but had not directly worked with until recently. I trained in basic immunology during my PhD, and during my clinical training, I became interested in bringing genetic diagnoses to the field of pediatric autoimmunity. My basic science training and my clinical interests have converged in my BBI project. Dr. King and her colleague Dr. Tom Walsh, the technology innovator of our group, enabled me to take on the challenge of genetics in autoimmunity and immune dysregulation, and now are helping me focus on the even more difficult problem of lupus.
Dr. King’s work integrates genetics as a classical way of thinking, based on families with children who are ill, with genomics as a set of modern tools to address the questions those families pose. This combination is particularly powerful in discovering the fundamental causes of lupus, which can appear in a different way in almost every one of my young patients.
With the support of the BBI, I am working to understand the causes of childhood lupus in my patients. I want to discover the exact mutations that have triggered their illness. Then I want to know how other mutations in the same genes trigger lupus in other children. Genetic influences in lupus have been recognized for more than 40 years, starting with the association of lupus with HLA antigens (human leukocyte antigens), with which so much fine work was done here in Seattle. But HLA types alone do not cause lupus. I hope to identify the driver mutations of each of my patients, mutations that are likely very rare or even private in genes that so far we know nothing about. I also want to know whether lupus is influenced by changes in the number of copies of critical receptors (the Fc-gamma receptor genes) that we do know something about. Then I want to integrate this information for the benefit of my patients.
BBI: How is that work going with your BBI catalytic collaborations grant?
Dr. Baxter: The Catalytic Collaborations grant gave me the opportunity to start building a partnership with Dr. Shaun Jackson, who has great expertise with B cells in lupus. He will test the functions of mutations I discover. His very sensitive tools for characterizing changes in cells are exactly what is needed for this project.
BBI: Where do you think this research might lead? How might it affect treatment or diagnosis options one day?
Dr. Baxter: I hope that in 5-10 years, I will be able to clinically test children with lupus for underlying causal mutations and use these genetic findings to tailor treatment. Nowadays, when we first diagnose a child with lupus, we prescribe a drug based on population studies – what has worked well in hundreds of other patients. Then in three to six months, we switch the drug or add another drug if the patient remains ill. In another two to three months, we repeat the process. Every few months, the patient comes back to the clinic, and the trial-and-error process continues. Our medications work slowly. We use very precise medications, but we apply them blindly. My hope is to use genetics to improve this process, and to change the paradigm from trial-and-error to precision medicine.