Precision Pathologist

by NORA DUNNE | photography by TERESA CRAWFORD

Daniel Brat is spearheading transformations in the field of pathology.

Though pathologists usually work behind the scenes in laboratories, rather than face-to-face with patients, their role in clinical care is crucial.

“It’s estimated that about three-fourths of the data in the electronic medical record is laboratory data and at least two-thirds of clinical decisions are influenced by laboratory results,” says Daniel Brat, MD, PhD, Feinberg’s new chair of Pathology.

Pathology is also a field that’s rapidly evolving, in parallel with advances in precision medicine and a trend toward sub-specialization. Brat, a neuropathologist who has spent nearly two decades studying diffuse gliomas, is spearheading this evolution within the arena of brain tumor diagnostics while straddling the line between scientific investigation and the practice of medicine.

“As the stewards of biospecimens, as well as the laboratory results and basic science findings that are derived from them, pathologists are in a prime position to advance understanding of human disease over the long term, while also supporting clinical care on a daily basis,” Brat says.

From Histology to Genomic Analysis

For more than a century, pathologists have diagnosed most diseases by looking at tissue samples under a microscope. By assessing the appearance and behavior of brain tumor cells, neuropathologists have classified and graded gliomas to help clinicians determine the best treatment plans for their patients. In 2015, Brat led a study conducted by a team of more than 300 scientists from 44 institutions worldwide challenging that status quo.

Listen Up:

Hear an interview with Brat in Feinberg’s new podcast series.

The investigators, part of the Cancer Genome Atlas Research Network, analyzed the genetic makeup of samples from 293 adults with a lower-grade glioma, a broad and clinically unpredictable class of brain tumor. Looking at molecular markers like mutations and gene deletions, the scientists were able to divide the tumors into three distinct subtypes associated with a tumor’s behavior and prognosis. These results, published in the New England Journal of Medicine, suggested that genetic status is a more accurate and consistent indicator of a tumor’s classification than the relatively subjective process of histologic evaluation.

“That study, among others, started a transformation that has been critical in our field,” Brat says. “We are now incorporating molecular findings into our primary diagnoses — making them definitional, rather than an association. That was a big step for us.”

In 2016, the World Health Organization (WHO) updated its international reference guide for classifying central nervous system tumors, outlining for the first time molecular parameters for defining tumors. Brat was a heavily involved co-author.

“The WHO doesn’t want to incorporate test results into their d­­iagnoses that the vast majority of the world doesn’t have the tools or expertise to actually perform,” he says. “However, it got to the point where we felt we were doing patients a disservice by not incorporating molecular alterations into primary diagnoses — we knew too much about the different behaviors of specific molecular subtypes of brain tumors.”

Brat is now leading national efforts to devise diagnostic and testing guidelines through the College of American Pathologists. He also travels the country spreading the word about these new findings, delivering presentations to hospital leadership and teaching continuing medical education courses to practitioners.

“Pathologists, neuro-oncologists, radiation oncologists and neurosurgeons are reading scientific papers and seeing reams of molecular profiles on hundreds of brain tumor patients with tens of thousands of markers being clustered by computer algorithms,” he says. “They need guidance on what practical clinical tests to perform to make these diagnoses.”

Classifying brain tumors is a theme that has marked Brat’s career since his early days as a fellow, when he first described a rare tumor now known as chordoid glioma. Over time it was accepted as a new entity by the WHO and found to have a specific genetic signature.

The next stage after characterizing genetic alterations of cancer is to understand how these influence biological behavior, so that we can devise better treatments.

“It’s been extremely satisfying seeing my findings get implemented broadly and improving clinical care worldwide. The whole process is eye-opening and a bit addictive,” he admits.

That thirst for discovery has made Brat an expert in his field.

“Dr. Brat is a recognized leader, both nationally and internationally,” says C. David James, PhD, professor of Neurological Surgery and a collaborator of Brat’s. “His research is at the forefront of the individualized medicine movement for tailoring cancer treatments to the unique characteristics of individual tumors.”

Brat earned his medical degree and a PhD in biomedical sciences from Mayo Medical School in 1994 and then completed his residency and a fellowship at Johns Hopkins Hospital. After training, he accepted a faculty position at Emory School of Medicine, where he remained for 17 years until joining Feinberg last September.

“Northwestern is a phenomenal institution, and I thought the pathology department, with the right resources and leadership, could become one of the nation’s best,” he says. Brat has also become a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “The brain tumor group here has had a really exceptional rise, both in the Chicago area and nationally, and I was thrilled to become a part of that.”

Though he was born in Detroit, and grew up in Minneapolis, Brat was also drawn to Northwestern and Chicago for personal reasons: His father, Paul Brat, ’63 MD, earned his medical degree here, and his mother currently lives in the city’s suburbs.

The Many Sides of Pathology

Broadly, the practice of pathology can be split into two branches: Anatomic pathologists examine biopsy and surgical resection specimens and make diagnoses based on what they see under the microscope in tandem with immunohistochemistry, molecular analysis and other tests. Meanwhile, clinical pathologists manage the laboratories that provide test results that help guide patient care. There are also many subspecialties within these branches, based on the kinds of samples or diseases examined.

“There’s been an explosion of information about disease that didn’t exist 30 years ago,” Brat says. “With cancer, for instance, it would be very difficult to be a generalist today with expertise in breast cancer, leukemia and lymphoma and brain tumor sub-classifications. It’s just too much information for a single mortal to carry.”

Feinberg’s Department of Pathology currently consists of 14 specialties, six main areas of research and nearly 100 faculty. As their leader, Brat plans to grow the department’s residency program, add four new fellowships — in gynecologic pathology, molecular pathology, transfusion medicine and microbiology — and continue recruiting and developing the faculty.

“Our faculty is extremely dedicated and talented. I’d like to shine a light on their successes, so they are more visible nationally and internationally,” he says.

Brat is also a strong proponent of the experimental side of pathology. The department has a collection of investigators focused primarily on mechanisms of inflammation, epithelial biology and cancer. In his own National Institutes of Health-funded basic science lab, Brat investigates the mechanisms that cause diffuse gliomas to progress.

“The next stage after characterizing genetic alterations of cancer is to understand how these influence biological behavior, so that we can devise better treatments,” he says. “Right now, a clinical study that demonstrates a two- or three-month increase in life expectancy for a patient with glioblastoma will get published in a very high profile journal. Big picture, that’s still a dismal prognosis. We’ve got a lot more work to do.”

In one project, his team is exploring how necrosis (cell death) and hypoxia (low oxygen) trigger rapid progression of glioma. In another, Brat’s lab uses drosophila (fruit flies) — a simplified genetic model — to study a gene that leads to brain tumor growth when deleted. Ironically, that gene is called “brain tumor,” or “BRAT” for short.

Stem cells have the ability to divide asymmetrically, leading to one daughter that is a stem cell while the other differentiates. The BRAT gene controls this process; without it, stem cells divide without differentiating, leading to overgrowth.

Top: Cheryl Olson, laboratory manager, and Subhas Mukherjee, PhD, research assistant professor of Pathology, with Brat in his lab. | Middle: Samples of brain tumor tissue in the “gross room” at Northwestern Memorial Hospital. | Bottom: Qinwen Mao, MD, PhD, associate professor of Pathology, and Alexa Derayunan, surgical pathology technologist, examine the samples with Brat to make a diagnosis.

“The fly brain tumor model is obviously not a model of human brain tumors, but there is an aspect of stem cell regulation that’s very relevant to human tumors,” Brat explains. “It’s thought that if you don’t eradicate that stem cell component in human brain tumors — only about 1 to 3 percent of their total cells — then tumors will recur like we know they do.”

His lab has identified a promising molecular target, a gene present in human gliomas called CDK5, that will reverse stem cell overgrowth in drosophila.

“It could lead to a more targeted therapy for the stem cell population in human tumors as well,” says Brat, who calls research his “creative outlet.”

For fun outside the lab, he watches his favorite sports teams — picking up more every time he moves — goes to movies and plays, and listens to classical music.

“But right now, I live four blocks away from work, which is a little bit dangerous, because I do love my job,” he says. “Pathologists really enjoy what they do, from providing expert diagnoses, to long days in the lab, to teaching the next generation of pathologists.”