The beauty and challenges of clinical biomarker research
When her daughter asked about the facts of life, Dr. Harriet Feilotter grabbed a napkin and drew pictures of chromosome segregation, mitosis and meiosis, “because that’s the part that I found really exciting.”
Today, as Laboratory Director of Molecular Genetics and Service Chief of Laboratory Genetics at Kingston General Hospital and Associate Professor, Dept. of Pathology & Molecular Science at Queen’s University, Kingston, ON, her clinical research focuses on validating new biomarkers for the screening, diagnosis and treatment of cancer. In her clinical practice, she uses tried-and-true biomarkers that detect disease and guide treatment decisions.
She diligently pursues the work that comes after biomarker discovery: the real-world implementation of new biomarker technologies. It’s a job that doesn’t have the same cachet as finding biomarkers, but without it, the clinical ability to use these pivotal discoveries wouldn’t exist.
It’s a fundamental step in transferring knowledge from bench to bedside that’s often overlooked by funding agencies.
Falling in love with the human genome
A Queen’s University biologist by training, Dr. Feilotter pursued her post-doctoral studies at Cold Spring Harbor, NY, where she lived next door to James Watson, the co-discoverer of DNA. She had an opportunity to work with him and other scientists on a search for genetic markers of psychiatric disorders.
“I was so intrigued that I completely jumped ship from studying yeast and cell proliferation to trying to understand the human genome and genetic markers of diseases as complicated as depression,” she explains. “That was a real eye-opening experience.”
She scrambled to get up to speed by taking courses in human genetics and molecular biology. Eventually, she opened a laboratory at Cold Spring Harbor to look for biomarkers of bipolar disorder.
“The idea that we could find physical markers that might predict whether somebody was at risk for this type of disease was amazing,” says Dr. Feilotter. “I just thought the whole question was a really interesting one.”
After returning to Canada with her husband, Queen’s cancer researcher Scott Davey, Dr. Feilotter began another search, for the next steps in her career. She enrolled in the Canadian College of Medical Geneticists (CCMG) program that trains professionals to work in the field of genetics in clinical settings, including hospital-based clinical laboratories. CCMG certification opened the door to her current posting at Queen’s.
Her clinical career is “based on the idea that biomarkers can tell us something about the risk or course of a disease and the likely response to therapy.”
In daily practice, her laboratory uses biomarkers to identify everything from monogenetic inherited diseases to somatic mutations in cancer cells.
Her clinical research focuses on evaluating biotechnologies that detect new biomarkers.
“Biomarkers are tricky to nail down,” she explains. “You need to be extremely careful when evaluating them, because they’re surrogate markers for something going on in the body. You need to put a biomarker through its paces to make sure that you know exactly how to measure it. If I measure it in my lab and you measure it in yours, we both need to get the same answers for the same patient.”
A biomarker can provide valuable information to clinicians and patients, but assay results need to be reliable or all bets are off. Taking a biomarker and “really grilling it” isn’t a sexy job, she says, but “it’s absolutely critical to get this right.”
However, she and other clinical scientists in this field face a real stumbling block. “Nobody wants to pick up the funding for this part of our job.”
The biomarker explosion meant that Dr. Feilotter’s laboratory often had to perform too many tests in too little time on tissue samples too small to satisfy the demand. So, she started looking for solutions.
Her clinical laboratory was one of the first in Canada to use a next-generation sequencing panel to detect about 50 defective genes at one time in solid tumours. Next-generation sequencing technology is a novel way to detect and measure massive numbers of biomarkers in the same tissue sample. This platform enables scientists to run hundreds, even thousands, of biomarker assays simultaneously.
But not all diseases are caused by single or point DNA mutations. Some happen when chromosomes split and fuse abnormally, a process called translocation. Then, there are copy number variants, which occur when large segments of a gene are mistakenly duplicated or deleted. Both genetic errors kick start the production of cancer-causing proteins.
While working with a European consortium, Dr. Feilotter came across an untried three-in-one biomarker assay that could simultaneously detect point mutations, translocations and copy number variants in a single tissue sample.
“I had worked on individual parts of that assay, but seeing it come together was very exciting,” she says. “This is the way we can get maximum information from tumour samples without having to go back and biopsy again.”
In an Ontario-based, cross-laboratory study, Dr. Feilotter has joined forces with Dr. John Bartlett from the Ontario Institute for Cancer Research to bring the new assay into clinical settings.
Their challenge was to find a way to fund its evaluation. They approached the product’s manufacturer, ThermoFisher Scientific, and offered to run the biomarker assay through its paces in clinical laboratories province-wide through industry partnership.
Dr. Feilotter doesn’t believe the project, now up and running at seven Ontario laboratories, would have received funding through traditional channels. “We saw an opportunity to move ahead, so we took it.”
Funding agencies get caught up in the hype of discovery, she explains. When scientists find a biomarker that reveals something new about a disease, that discovery generates a lot of excitement. But no one thinks about what happens next.
“There’s an assumption that, boom, we’re able to measure the biomarker in the lab. Just like that. People don’t appreciate that there are as many ways to measure a biomarker as there are people trying to do it.”
Differences in processing and interpreting biomarker assays can profoundly alter results, she explains, particularly if no standardized laboratory procedures exist. “Few people want to put in any elbow work into figuring that out across labs.”
This project may provide a way to implement and standardize biomarker protocols at provincial clinical laboratories to improve quality control and reduce costs, she believes.
“It’s a fantastic opportunity for us to step up to the plate.”