Investing in the Power of Pathology and Genomics

A $2 million grant from the Mass Life Sciences Center has helped launch the Comparative Pathology and Genomics Shared Resource at Cummings School of Veterinary Medicine, a shared resource with state-of-the-art equipment that fills newly renovated laboratory space. For Cheryl London, a veterinary oncologist and Associate Dean for Research and Graduate Education, it represents a long-time vision becoming reality.

“Understanding the pathology of infectious diseases is more critical than ever,” said London, who added that the resource will lead to improvements in the treatment and prevention of diseases in humans through detailed genetic characterization of model systems and the associated pathology across species.

London tapped two Cummings School faculty members to lead the effort: assistant professor Amanda Martinot, a veterinary pathologist who focuses on infectious diseases such as SARS CoV-2 and tuberculosis, and assistant research professor Heather Gardner, GBS20, a veterinary oncologist and geneticist.

Cummings School has been investing in this goal for quite some time. In 2020, the 7,500-square-foot Peabody Pavilion was renovated into modern, flexible lab space designed to support multidisciplinary teams. In addition, the resource will leverage Tufts resources such as the New England Regional Biosafety Laboratory (RBL).

“When fully operational, this resource will offer advanced capacities for credentialling and analyzing animal models of disease that will help to grow collaborative opportunities among regional academic and industry entities; provide training opportunities for students, fellows, scientists and clinicians; and ultimately support job growth through expansion of the research enterprise in Central Massachusetts,” said London.

Projects in the Pipeline

Martinot’s research has focused on tuberculosis (TB). When the Martinot Lab and her collaborators—Cummings School assistant professor Gillian Beamer, Tufts University School of Medicine associate professor Bree Aldridge, and Harvard University professor Peter Sorger, head of the Harvard Program in Therapeutic Sciences—identified some rare lung biopsies and archived lung specimens from tuberculosis patients that were taken during autopsies many years ago, Martinot thought they were a natural pilot project for the Comparative Pathology and Genomics Shared Resource.

“With the help of this grant, we can do whole genome sequencing for genetic analysis of pathogens, tumors, and anything imaginable where the DNA sequence might make a difference," said veterinary pathologist Amanda Martinot. Photo: Jake Belcher for Tufts University

“We're trying to understand the biology of tuberculosis in human tissue, what helps the body clear TB, and what fuels TB progression,” said Martinot. “We use a lot of animal models to try to understand these processes, but there's no animal model that perfectly mimics human TB disease.”

The resource’s new technology can extract meaningful genetic information from the immune cells surrounding and within granulomas, a hallmark pathologic feature of tuberculosis—something they haven't been able to do before. This technology also will allow them to obtain similar information from a variety of pathology samples.

Another pilot project aims to advance research by London and Gardner in canine osteosarcoma, an aggressive bone cancer that affects more than 25,000 dogs each year. In 2019, they published findings of a study that detailed the landscape of genetic mutations in canine osteosarcoma, and more recently completed a clinical trial to test a new immunotherapy treatment on dogs diagnosed with this type of cancer. The Clinical Trials Office at Cummings School has treated a number of canine osteosarcoma patients, allowing banking of associated biologic samples for further investigation. With these tissue samples, investigators can ask questions about the molecular and genomic features of cancer over time and identify clinical and pathologic correlates.

“Animals get a lot of the same diseases that people do, and the information we learn from animals with these diseases can inform investigation of novel research opportunities across species,” said Gardner.

“We can start to interrogate the combination of pathology with genetics and follow how the cancer is mutating,” Martinot said. “And we can look at where these cancer cells live to try to understand how the microenvironment might be supporting the progression of the cancer. That information could lead to potential treatment options.”

Paul Mathew, an oncologist at Tufts Medical Center and an associate professor at Tufts School of Medicine, is interested in using the resource’s technology to ask similar questions about prostate cancer using biopsies from human patients. He wants to understand the tumor and how the microenvironment changes over time in prostate cancer patients. The School of Medicine is one of many potential users of the resource—others include UMass Medical School and Medical Center, which has plans for a new Veterans Administration outpatient clinic and Institute for Human Genetics.

“The opportunities to impact research, in all areas, are limited by the investigators’ imagination," said Heather Gardner, GBS20, a veterinary oncologist and geneticist. Photo: Jake Belcher for Tufts University

The Technology Inside

The resource is home to “cutting edge new technology that integrates pathology and genomics,” said Martinot. “With the help of this grant, we can do whole genome sequencing for genetic analysis of pathogens, tumors, and anything imaginable where the DNA sequence might make a difference.”

The goal is to help drive discovery, adds Gardner. “We have equipment to support next generation sequencing projects, such as a liquid handler robot to help automate sample processing and an Illumina sequencer. We also have a suite of NanoString equipment, which is a platform that will allow increased use of samples historically considered difficult to work with, including formalin-fixed samples, which are often very degraded.”

The new technology that will power this effort falls into two main categories:

• Highly multiplexed immunofluorescence imaging, which combines the microscopic study of tissue samples with high-dimensionality analysis tools. Martinot’s lab members are currently training in the Sorger Laboratory at Harvard to apply a specific form of this technology, tissue cyclic immunofluorescence (t-CyCIF), to animal models of infectious disease.
• Next Generation Sequencing and Nanostring Technology, which includes short-read sequencing, single-cell sequencing, and digital spatial profiling capabilities.

Everyone involved with the shared resource is excited about its future potential and the opportunity to see it grow. As Gardner said, “The opportunities to impact research, in all areas, are limited by the investigators’ imagination.”

Angela Nelson can be reached at angela.nelson@tufts.edu.