Dr. Tamas Ordog wants to find the needle in the haystack without grinding up all the hay — and he's doing it by mapping tumors one cell at a time.
Finding the exact cause of a patient's cancer has traditionally been like searching for a needle in a haystack — and worse, the standard methods often required destroying the very tissue being studied. But what if doctors could examine every cell in a tumor while keeping track of exactly where each one sits, mapping out how they interact with their neighbors in three dimensions? That's the promise of spatial transcriptomics, a leading-edge technology that Tamas Ordog, M.D., and his team at Mayo Clinic are bringing to patient care.
After doing his medical training in his native country of Hungary, Dr. Ordog studied neuroendocrine biology, touching on topics like electrical signals in the hypothalamus regulating the menstrual cycle. He started as a junior faculty member at the University of Nevada, Reno, before coming to Mayo Clinic in 2006. In 2012, he helped found the Epigenomics Program at the Mayo Clinic Center for Individualized Medicine. In 2020, he moved to work with the Center for Cell Signaling in Gastroenterology.
Now he and Jeong-Heon Lee, Ph.D., are hard at work creating a first-of-its-kind research enterprise: a core dedicated entirely to spatial biology.
“‘Spatial’ is a little bit of a misleading term,” says Dr. Ordog, “because currently almost everything we do is in two dimensions [like flat X-rays of body parts], but there is no theoretical limit to why anything we discover doesn’t apply in 3D.”
Spatial biology is essentially what it sounds like: the study of tissues, cells and genes put into terms of how they relate to each other in three dimensions. Think of an organ or a tumor as a complex city, where each cell is a building with its own role and relationships to its neighbors. Some cells might be driving a disease, while others are trying to fight it off. Traditional methods could tell us what types of buildings existed in the city, but not how they are arranged or how they influence each other. Spatial biology changes that by creating a detailed 3D map of every cell in a tissue sample, showing not just what genes each cell is expressing, but how those cells work together — or against each other — in the complex ecosystem of a complete tissue.
Drs. Ordog and Lee make a top-notch team. Dr. Ordog brought Dr. Lee, then a postdoctoral researcher at Indiana University, to Mayo Clinic to tune the technology he developed there toward human health applications. Dr. Lee’s primary focus now is an area called spatial transcriptomics, studying how gene expression in one cell affects gene expression in its neighbors.
“The ultimate goal is to build a 3D model of any tissue we study, providing information about how the cells are positioned relative to each other and how they behave — as in what genes and molecules they express,” says Dr. Ordog.
Molecules and genes are just the beginning. To Drs. Lee and Ordog, spatial biology isn’t just about the relationship between cells in one modality, but in all the ways they can relate to one another — their genes, their proteins, the ways they contact one another, cells dividing in one region and dying in another. Dr. Ordog calls this “spatial multiomics,” combining different techniques in the same space.
“We want these to be more than the sum of their modalities,” says Dr. Ordog. “The goal is to bring all these elements — the study of genes, molecules, proteins, etc. — into all relevant tissues.”
Bringing together all these different scientific threads will help Mayo Clinic do something completely unprecedented: create a whole new kind of pathology.
“Spatial biology shortens the translational pipeline,” says Dr. Ordog. Rather than needing to start with preclinical models, doctors and researchers can now start primary discovery with a tissue biopsy or surgical materials directly from a patient. They are looking for the needle in the haystack that might lead to a new discovery or therapy.
The bottom line is that we want to increase the amount of information gathered from the precious biopsy material taken from our patients.
— Tamas Ordog, M.D.
“That’s what modern biology has enabled. You can pick out your molecule of interest based on whatever you’re studying,” says Dr. Lee. “You can study diseased versus not-diseased tissues. Say you discover molecules in diseased state that aren’t in healthy tissues, that’s your target.” Then scientists can go back to the lab and examine what they’ve discovered in other models to look for treatment options, armed with the knowledge that what they have found is directly involved in a patient’s health.
Dr. Ordog envisions a “virtual patient vignette”: A patient comes in with a form of cancer that comes in multiple forms, each with different prognoses, signs of progression and immune cell profiles, and each responds to different therapies. In the past this would be a dizzying knot to untie, but with spatial multiomics, it becomes clearer. A biopsy taken from the patient is serially chopped into sections, each of which gets processed a different way. Then the data is put back together into a three-dimensional image.
Instead of trying different therapies to see what works, clinicians could use this approach to examine the tumor's cellular architecture and predict which treatment would be most effective, saving precious time in the fight against cancer.
“The bottom line is that we want to increase the amount of information gathered from the precious biopsy material taken from our patients,” says Dr. Ordog. “Spatial biology can increase the understanding that comes out of the tissue exponentially.” That, in turn, can allow for in-depth machine learning and artificial intelligence analysis of patient data, which Dr. Ordog hopes to test sometime in the future.
All in all, Dr. Ordog, Dr. Lee and the entire team are hopeful their work will simplify the detective work that doctors and patients often experience when hunting for a diagnosis or treatment. Looking over a slide deck he uses to explain the technology, Dr. Ordog sounds a hopeful note.
“We can find the needle in the haystack without having to grind all the hay up.”
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