Filling a Need in Infectious Disease Research

One year after opening a Comparative Pathology and Genomics Shared Resource (CPGSR), which provides detailed assessments of animal models of disease, Cummings School of Veterinary Medicine at Tufts University has carved out a unique regional niche for its services.

Supported by a $2 million grant from the Massachusetts Life Science Center (MLSC), Cummings School developed the CPGSR, which aims to improve human and veterinary translational outcomes (i.e., treatment and prevention) through its work across several species at the clinical, pathologic, and genomic levels.

Cummings School’s renovation of its Amelia Peabody Pavilion, which houses the CPGSR, coincided with the MLSC grant, according to Dr. Cheryl London, V90 (she/her), director of Clinical Research Shared Resource, who spearheaded the effort to secure the MLSC grant.

“The MLSC is working to expand the biomedical research footprint in Massachusetts beyond the area inside [Route] 128, which is saturated,” London explains. “They perceive, and I agree, that there is significant opportunity for growth in the technologies, resources, and workforce in this area of the state and by creating those capacities, it will attract more businesses to this area, facilitating growth of the academic enterprise and expanding opportunities.”

The CPGSR is co-directed by Dr. Amanda Martinot (she/her), a board-certified veterinary pathologist, and Dr. Heather Gardner, VG20 (she/her), a board-certified veterinary oncologist specializing in genetics. 

A need for services

“This facility addresses a regional need for advanced capacities designed to link pathology and genomics data and expertise. What has changed in comparative pathology is our ability to do a much deeper dive into the cellular, molecular, and genomic landscape of pathology specimens, with the ultimate goal of  characterizing them more precisely,” says London. 

“For example, a limitation associated with pathology specimens is that we can stain them with specific antibodies to look for certain proteins, but typically only 4-6 antibodies can be used at any one time. Now we can conduct studies using spatial multi-omics, where we can dissect what cells in one area of the tissue are doing in relation to cells in another area of the section, creating a roadmap of cell interactions.  For example, we can tag specific immune cells in a tumor to determine what genes and proteins  they are expressing to assess how this varies across the tumor (i.e., immune cells within the tumor versus outside the tumor).”

The advanced technologies available have also enabled investigators to ask questions about cells on a single-cell level, which provides much more detail about their behavior, according to London. “This enables us to fully credential and validate animal models of disease as relevant for human comparison. Then we can ask ‘Do they really represent what we see in humans at all levels (cellular, molecular, or genomic)?’”

New technologies in the CPGSR also permit investigators to more accurately follow disease longitudinally within individual animals over time, as these assays may only require very small samples. The difference is striking. “Essentially, instead of having a ‘10x’ view, we now have a ‘1,000x’ view to see what’s happening,” London says. “Importantly, it has provided a mechanism for us to leverage our unique veterinary expertise across pathology and genetics, and provide crucial information that will ultimately help improve the successful development of new treatments for a variety of diseases, providing an advantage over other local entities with similar instruments.

Services offered prior to the CPGSR

Years ago, Cummings School operated a discovery pathology histology service through the hospital pathology diagnostic lab which offered many of the routine services used for diagnosis of disease in companion animals for research animals, according to Martinot, who also runs her own lab in the Department of Infectious Disease and Global Health as a principal investigator, The Martinot Lab – discovery pathology for infectious disease and vaccine research.

“Clinical tissue samples that needed to be analyzed to diagnose cancer or other diseases in our veterinary patients were going through the same workflow in the diagnostic lab as research samples, with clinical samples being prioritized,” says Martinot.  

When COVID-19 began, a large influx of tissue analysis requests were being received from COVID-19 researchers that were high priority, which created a bottleneck, of sorts. A separate research pathology lab was needed on campus to manage the increased workflow. Since the hospital had to slow down during the pandemic, and the technicians in the diagnostic lab were available for research, Martinot took the opportunity to expand research pathology at Cummings School.

Comparative pathology upgrade

“As we looked to resurrect our discovery pathology service, we aimed to separate it from the diagnostic lab so we could prioritize research and processing samples,” Martinot explains. “In addition to our need at Cummings School, this also addressed a regional need, as there are few pathology laboratories available locally that provide similar types of services [e.g. Hemotoxylin and Eosin (H&E) staining, immunohistochemistry (IHC), tissue sectioning, and histopathology scoring] to outside investigators. We are now offering those through a designated research pathology core.”

The CPGSR is supported by two full-time histotechnicians, a lab manager, and a molecular biologist to fulfill the request for services. “We’re the only academic institution in MetroWest [Boston] offering these as a fee-for-service,” Martinot says, pointing out that automated machines enable the team to efficiently complete H&E staining and IHC requests.

The MLSC grant monies enable the CPGSR to offer research services such as sequencing of pathogens and tissues, the sequencing of tumors to analyze their evolution, as well as supporting research studies from the School’s clinical trials unit. 

“There are several new technologies within the realm of spatial transcriptomics, which involves obtaining gene expression information from specific regions in a tissue,” Martinot shares. “These methodologies require involvement of veterinary pathologists in addition to genomics expertise.” 

Martinot offers consultations to outside companies and investigators regularly. “Many of the services we provide involve time-consuming dynamic processes as some can be quite expensive (i.e., $10-20,000).  Therefore, we work with them to plan out the most cost effective approach for asking and answering key questions using their tissue samples.” 

Genomics and sequencing

A wide breadth of options for services are available from CPGSR’s genomics arm, according to Gardner. “We handle anything from nucleic acid extraction, sample QC, library prep and bulk and single-cell sequencing, and spatial transcriptomics.”

A robot enables the automation of many processes, while aiding accuracy, efficiency, and consistency between batches. Under Gardner’s direction, a full-time molecular biologist is solely dedicated to overseeing the genomic assays, supported by a part-time associate.

“Because we may be working in non-target species (i.e., beyond mouse and human), assays may need to be optimized first, before the intended samples can be appropriately analyzed,” Gardner explains.

Cummings School’s breadth of expertise across a variety of species provides a distinct advantage in comparison to other service providers, according to London. “We have experience with many animal model systems, ranging from mice to hamsters, to dogs, and up to primates and humans,” she says. “We’re uniquely positioned to work with a multitude of species and bridge our foundational knowledge across pathology and genomics to better address needs of investigators that may be working in non-traditional model systems.”

CPGSR’s focus and its future

While much of the work in the CPGSR is focused on infectious disease and comparative oncology, application of the technologies available is slowly growing to include autoimmune and cardiac diseases, among others. “Part of what we do is determine whether a model system being used to study a disease accurately reflects the human counterpart, as this is necessary for that system to generate information that has translational capacity,” says Martinot. 

Although service requests are completed by highly trained professionals, Cummings School is also committed to training the next generation of veterinary pathologists, engaged in translational and biomedical research. Veterinary students are being trained through a digital pathology elective offered by Martinot and a summer research program, in addition to ongoing oncology and surgery resident training in pathology, and the education of master’s and Ph.D. graduate students.

Looking ahead, CPGSR is working to expand and integrate animal research with Tufts University School of Medicine and Tufts Medical Center (TMC). Martinot explains, “We are now offering histopathology support to complement TMC comparative medicine and complement the genomics sequencing offered by the TMC sequencing core. Our services address different research priorities.”

Martinot sees much room for growth. “We’re starting to see rising interest in single-cell work and spatial transcriptomics, in particular,” she says. “Those are hot and growing areas in multiple research sectors, so there’s a lot of interest in having those capabilities in central Massachusetts. We hope to attract more projects so we can put our advanced technology to work.”

The CPGSR is housed within the Department of Comparative Pathobiology (CPB), where Martinot and Gardner have secondary faculty appointments. Pathologists with primary appointments in the CPB provide veterinary diagnostic service through the Cummings Veterinary Diagnostic Lab. 

To request services from the CPGSR, (open M–F, 8 am–4 pm) visit its online platform.