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Mayo Clinic Medical Science Blog – an eclectic collection of research- and research education-related stories: feature stories, mini news bites, learning opportunities, profiles and more from Mayo Clinic.

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Wed, Sep 16 6:00am · Mayo Clinic research advances diagnostics to lead COVID-19 pandemic response

Advanced Diagnostic Laboratory scientists on the neutralizing antibodies team: Jennifer Rysavy, Amy Gorsh, Jack Wu, Ellen Lexvold

When COVID-19 spread across the U.S. in early March, Mayo Clinic’s Advanced Diagnostic Laboratory (ADL) urgently responded. Lab spaces were transitioned, staff reassigned and funding approvals were fast-tracked. Its goals were to accelerate research, development, translation and implementation of novel tests in order to discover life-saving treatments and diagnostics.

“ADL houses a lab structure for clinical investigators to evaluate new technologies, advance analytics and to foster collaboration between outside companies and Mayo investigators to support the clinical practice,” says Benjamin Kipp, Ph.D., director of the Advanced Diagnostics Laboratory.  

The nimble structure of the laboratory, which is jointly supported by Mayo Clinic’s Department of Laboratory Medicine and Pathology and the Center for Individualized Medicine, allows the researchers to be flexible and quickly respond to the emergent pandemic.

Six months in, teams of Mayo scientists are at the forefront of innovative COVID-19 diagnostics, working to unravel the complexities of the novel virus and diagnose it quickly. Some of the teams’ innovations include antibody (blood) and viral antigen testing, patient immune response stratification, point-of-care diagnostic testing, tissue diagnostics, self-collection kits and data analytics/bioinformatics, to name a few. 

“I am pleased that many of our Mayo colleagues have utilized the lab to evaluate many unique COVID-related tests and I am grateful that a few of these tests have recently been transferred to the clinical laboratories to help patients,” Dr. Kipp says.

Combatting Covid-19 with innovative tests

ADL Team Neutralizing Antibodies: Lisa Morelli, Calvin Jerde, Matt Roforth, Dr. Mills, Ted Stier

COVID-19 test developments are transpiring inside the state-of-the-art laboratory in One Discovery Square, located in the heart of downtown Rochester, Minn., where highly specialized teams of pathologists, clinical laboratory scientists, technologists, project managers and other experts, focus on specific clinical applications.

Tracking neutralizing antibodies

In one major milestone, scientists in the Advanced Diagnostic Laboratory have developed a SARS-CoV-2 neutralizing antibody test in support of nationwide efforts to find treatments and vaccines for COVID-19. The new test measures the level of neutralizing antibodies against SARS-CoV-2. Neutralizing antibodies represent those antibodies that can inactivate viruses and have been demonstrated to provide immunity against reinfection in other infectious pathogens. Studies to understand protective immunity in SARS-CoV-2 are ongoing.  Plans are underway to develop a second version of the assay to improve performance and throughput.   

John Mills, Ph.D., co-director of the Neuroimmunology Lab, was brought in to lead the team, with support from Elitza Theel, Ph.D., director of the Infectious Diseases Serology lab, and in collaboration with Stephen Russell, M.D., Ph.D., a Mayo Clinic colleague and entrepreneur at Vyriad, Inc.

“The neutralizing antibody test is a critical addition to our COVID-19 testing, expanding on the capabilities of the molecular tests used to diagnose active infection and the serology test, which indicates previous infection by identifying antibodies for the SARS-CoV-2 virus,” says William Morice II, M.D., Ph.D., chair of the Department of Laboratory Medicine and Pathology and president of Mayo Clinic Laboratories.

Detecting SARS-CoV-2 exposure with dried blood spots

Dried Blood Spot Team: Caroline Kleppe

Another approach for large scale testing involves validating dried blood spots as a specimen source for self-collection. Dried blood spots have been used in newborn screening since the 1960s, intermittently also to detect antibodies (e.g. HIV). A laboratory group involved in innovation has validated the use of this material for serology testing to determine if a patient has been exposed to SARS-CoV-2.  This was launched in June and was used to provide testing for more than 30,000 Mayo employees as part of a seroprevalence study. 

“The validation of the use of dried blood spots with serology testing was an overall team effort including people of different backgrounds, and most of whom still have never met in person but are united in our commitment to meet the need of patients here, there and everywhere, including their own homes,” says Dietrich Matern, M.D. Ph.D., co-director of the Biochemical Genetics Laboratory, Division of Laboratory Genetics and Genomics.

Repurposing existing technology

In another test project, Advanced Diagnostic Laboratory researchers are using existing technology, digital droplet PCR (ddPCR), to see if it would be more sensitive than current qPCR technologies for the detection of SARS-CoV-2 and whether having a quantitative viral measurement would monitor patients’ natural progression of COVID-19 and response to therapy. Lab staff used different reagents to avoid supply chain challenges.  

With the support of Joseph Yao, M.D., director of the Hepatitis/HIV Serology Laboratory, and Ann M. Moyer, M.D., Ph.D., co-director of the Personalized Genomics Laboratory, the quantitative SAR-CoV-2 RNA test by ddPCR has now been developed and offered for research use with strong interest from the biopharmaceutical market to help in drug development. 

Launching at-home self-collection tests

Another innovation project is focused on self-collection devices for molecular and serologic testing . These validated collection procedures would make testing more accessible to patients and open up opportunities for direct-to-consumer and consumer-initiated channels for Mayo Clinic Laboratories.

“The team is evaluating the use of a mid-turbinate nasal swab, which is 3D printed at Mayo,” says Bobbie Pritt, M.D., division chair of Clinical Microbiology. “The 3D printed swabs serve to mitigate the risk from future supply chain shortages of the commercially available swabs.” 

Redefining innovation to combat COVID-19

The Advanced Diagnostic Laboratory seeks to provide an understanding of COVID-19 and minimize its impacts on the needs of the patients when it comes to laboratory testing. The neutralizing antibody test was its first to go through the lab from inception to test implementation. The test serves as a “how to” guide in developing new tests in a safe, innovative and timely manner. These advances are possible through the collaborative team effort within the lab.

“I have been thoroughly impressed with the teamwork displayed by all the different COVID innovation teams during this pandemic and expect continued success moving forward,” Dr. Kipp says.

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This article was originally published on the Center for Individualized Medicine blog.

Tue, Aug 4 6:00am · Phage therapy shows potential for treating prosthetic joint infections

Bacteriophages are naturally occurring viruses that destroy bacteria by injecting their DNA or RNA into the bacteria to replicate and burst the cells open.

Bacteriophages, or phages, may play a significant role in treating complex bacterial infections in prosthetic joints, according to new Mayo Clinic research. The findings suggest phage therapy could provide a potential treatment for managing such infections, including those involving antibiotic-resistant microbes.

The research is published in the July 23 issue of Clinical Infectious Diseases (CID).

“The treatment for chronic prosthetic joint infection has been surgery plus antibiotics, with surgery being the backbone of therapy. When these efforts fail, there can be significant suffering, loss of limb, and even death,” says author Gina Suh, M.D., Mayo Clinic infectious diseases specialist. “Phage therapy has the potential to be paradigm-shifting in how we treat infections in this era of increasing medical device use and antibiotic resistance.”

Phages target and kill specific bacterial cells, including those that have grown resistant to multiple antibiotics.

Phages are naturally occurring viruses found throughout the earth that target and kill specific bacterial cells, including those that have grown resistant to multiple antibiotics. The microscopic organisms, numbering in the billions, destroy bacteria by injecting their DNA or RNA into the bacteria to replicate and burst the cells open.

“Phage therapy has the potential to be paradigm-shifting in how we treat infections in this era of increasing medical device use and antibiotic resistance.”

Gina Suh, M.D.

Although phage therapy is new to Mayo Clinic, the bacterial predators were discovered more than a century ago, predating antibiotics. Today, much of the basic science of phages remains to be discovered.

Dr. Suh oversaw the first phage treatment at Mayo Clinic in June 2019, when a 62-year-old man was facing potential amputation after multiple failed courses of antibiotics and surgery. The intravenous use of phage therapy was approved by the U.S. Food and Drug Administration on a compassionate-use basis.

Gina Suh, M.D., Mayo Clinic infectious diseases specialist

“We started phage therapy as kind of a last-ditch effort to save his limb, and the patient responded beautifully,” Dr. Suh says. “He has remained asymptomatic after completing treatment and he experienced no adverse effects.”

The patient’s infection involved a biofilm that formed on his knee-joint replacement device — a common complication among the millions of people worldwide who undergo life-enhancing joint replacements every year.

Study co-author Robin Patel, M.D., says biofilms are communities of bacteria held together in a slimelike substance and that growth in biofilms enables bacteria to evade the effects of many antibiotics.

“We’re looking for the ability of phage to either kill or keep these bacteria from growing as a measure of activity.”

Robin Patel, M.D.

“When bacteria grow as biofilms on surfaces, such as joint replacement devices, bacteria are difficult to eradicate because being in biofilm state makes them resistant to many of the antibiotics that would otherwise work against them,” says Dr. Patel, who is also the director of Mayo Clinic’s Infectious Diseases Research Laboratory.

Dr. Patel uses proteomic analysis to identify a patient’s bacterium to begin the process of matching it with a phage.

“We then test a collection of phage against that particular patient’s species of bacteria to determine which might work best,” Dr. Patel says. “We’re looking for the ability of phage to either kill or keep these bacteria from growing as a measure of activity.”

She says as the world faces a growing public health threat from drug-resistant bacterial infections, and that it is possible  phage therapy could save lives, but more study is needed.

“There have been several patients who have been treated with phage with promising outcomes, but as a scientist, a single case like ours, or even a collection of single cases, is not enough to prove that a therapy is active,” Dr. Patel says.

Robin Patel, M.D., director, Mayo Clinic’s Infectious Diseases Research Laboratory

The next step in the study is to expand the clinical use of phage therapy on prosthetic-joint infections of the hip and knee. Mayo Clinic is launching a two-year clinical trial later this year to continue to evaluate phage therapy in the treatment of infectious diseases.

This research was done in collaboration with Stanford University School of Medicine; Adaptive Phage Therapeutics, and the Naval Medical Research Center.

The research was funded in part by the Congressionally Directed Medical Research Program (Work Unit Number A1427), Naval Medical Research Center, and by the Mayo Clinic Center for Clinical and Translational Studies through grant number UL1TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH).

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This article was originally published on the Mayo Clinic Center for Individualized Medicine blog.

Tue, May 26 6:00am · AI enhances MRI images to identify molecular markers of brain cancer

By Sharon Rosen

Five years ago Bradley Erickson, M.D., Ph.D. never would have imagined that an MRI would be able to identify the molecular characteristics of brain cancer. But because of the rapid advances in artificial intelligence (AI), that scenario isn’t science fiction. It’s an exciting medical reality for Dr. Erickson, a radiologist on Mayo Clinic’s campus in Rochester, Minnesota and his colleagues. With support from the Mayo Clinic Center for Individualized Medicine Imaging Biomarker Discovery Program, the team conducted a study in which AI tools rapidly scanned MRI images and successfully identified molecular markers for patients with glioma, a type of brain cancer, with more than 90% accuracy.

According to Dr. Erickson, this technology introduces a new type of precision medicine based on imaging.

“As these tools are refined, I can imagine a work flow where we input an image into a computer, which generates molecular markers of a patient’s cancer — things we previously thought required taking tumor samples for pathology analysis,” says Dr. Erickson, “Based on those markers, we can select the best targeted agent for a patient. We may also be able to monitor treatment response with this same process.”

Here’s a closer look at how Dr. Erickson and his team are using AI to enhance the interpretation of images of brain cancer and other diseases.

Deep learning tool plays key role in patient care

In the study, investigators analyzed images from The Cancer Imaging Archive, a National Cancer Institute initiative that includes images submitted from multiple centers, including Mayo Clinic. Researchers analyzed MRI images from 500 patients with glioma with an AI tool known as deep learning.

Using images from 400 of the patients, researchers first “trained” the deep learning tool to recognize four molecular markers of glioma. These biomarkers, which were established by the World Health Organization, can help predict how a tumor will behave and identify the most effective targeted therapies.

Researchers then imputed images for the remaining 100 patients. The deep learning tool successfully predicted molecular markers, which had previously been identified through genetic testing, for the majority of patients.

“While these AI tools won’t replace genomic or pathology testing, they will provide important information about a patient’s disease that can be used along with other measures to develop an individualized treatment plan,” says Dr. Erickson.

The next step is to move this technology into patient care to analyze MRI images for glioma patients.

“If our findings agree with genetic testing and pathology results, we can be more confident that we have correctly classified a patient’s disease and can move forward with an individualized plan for care,” says Dr. Erickson. “If imaging results differ from genetic and pathology findings, this may signal the need to watch a patient more closely when selecting a targeted therapy and monitoring treatment response.”

The deep learning tool will also play a key role in identifying a patient’s disease type when a tumor sample cannot be obtained.

“In cases where the tumor size or location makes it difficult to obtain a tissue sample, our computer models can still offer a characterization of a patient’s disease,” says Dr. Erickson.

Dr. Erickson notes that similar computer models are already being used to enhance imaging in other areas of Mayo Clinic patient care.

For example, radiologists are able to more accurately and rapidly measure the volume of kidney cysts for patients with polycystic kidney disease. This is a crucial measurement when evaluating treatment options and response to therapy.

According to Kiaran McGee, Ph.D., director of the Imaging Biomarker Discovery Program, “Dr. Erickson’s work is a great example of how AI is impacting clinical medical decision making processes in a real and tangible way.”

AI serves as springboard for discovery

“It’s an exciting time — AI is revolutionizing the way we are able to analyze images, with a growing number of examples where biological traits are revealed that it would have taken a human months to identify or that had never been seen,” Dr. Erickson explains.

He points to the potential that the deep learning tool will have as a springboard for discovery.

“We used to think these computer models were black boxes. We weren’t sure what the computer was seeing. Now we have a better understanding of the technology and can apply it to make discoveries about underlying features of disease that were previously unknown. This may unlock new ways to prevent, diagnose, treat and even cure disease,” adds Dr. Erickson. 

Thu, Apr 30 6:00am · Mayo researchers' endometrial cancer discovery could lead to window of opportunity for prevention

What if a doctor could alert a woman a year or more in advance that she is likely to develop endometrial cancer? Researchers at Mayo Clinic Center for Individualized Medicine have found evidence linking functional modification of certain genes to the emergence of the disease, providing a novel opportunity for intervention and prevention.

The new finding, reported in the journal Gynecologic Oncology, is far-reaching, both to the basic understanding of endometrial cancer — affecting more than 600,000 women in the U.S. — and for the search for preventative measures. Endometrial cancer is the fourth most common cancer in women, with nearly 62,000 new cases and 12,000 deaths estimated in 2019. Incidence rates are expected to rise significantly over the next decade, driven by environmental factors, obesity and diabetes.

“We found that some of the epigenetic markers that are known to be associated with endometrial cancer are altered months to years before the development of the disease,” says Marina Walther-Antonio, Ph.D. “Patients who have increased methylation in particular genes in benign endometrial biopsies are more likely to develop endometrial cancer in the future.”

Flipping the switch: finding genes that have been “turned off”

Dr. Walther-Antonio says “epigenetic markers” are changes in gene activity that control the functional gene level and can effectively turn the gene “on” or “off.” 

“In this sense, the gene can be free of mutations, yet be in practice, non-functional — equivalent to a perfectly functional car that will not respond to the accelerator pedal because the key is not turned on in the ignition,” she describes.

“We found that some of the epigenetic markers that are known to be associated with endometrial cancer are altered months to years before the development of the disease.”

Dr. Walther-Antonio

Marina Walther-Antonio, Ph.D.

Methylation, she explains, is in this analogy, controlling the position of the key in the ignition. This disruption of gene functioning through epigenetic processes such as methylation can be a hallmark of cancer.

The research team studied samples of women over nine years whose endometrial biopsies were benign, but subsequently developed endometrial cancer an average of one year later. To demonstrate their hypothesis, the team studied the promoters of four particular genes that are reported as hypermethylated in endometrial cancer. Which, in this case, is turning the key in the ignition to an “off” position, and in effect, shutting the gene function down.

“We could see that the women who developed cancer in the future were already different at the time of the biopsy,” Dr. Walther-Antonio explains. “They already presented a hypermethylated state in these genes back then.”

Discovering a missed opportunity for prevention

Co-author of the study, Andrea Mariani, M.D., a gynecology oncologist surgeon who has conducted extensive research on endometrial cancer over two decades, says he developed the study in hopes of discovering this “missed opportunity for prevention.”

“Post-menopausal women would go to the doctor because of bleeding, and they would get a biopsy of their uterus and the biopsy was benign, and then sometime down the road they developed endometrial cancer,” he says. “We call this a missed opportunity.”

Andrea Mariani, M.D. M.S.

Dr. Mariani previously demonstrated that as many as 28% of endometrial cancer patients had a previous non-malignant endometrial biopsy during their lifetime.

“This means that approximately one quarter of endometrial cancers can be potentially prevented if we target this population,” he explains. 

In his search for answers, Dr. Mariani, who also serves on Mayo Clinic Robotics Subcommittee and collaborates on the use of robotic surgery for the treatment of endometrial cancer, pulled together a team of scientists to combine their expertise.

“I am a physician, I am a surgeon, and I can help define where we need to go, but then we need people like Dr. Walther-Antonio and the other scientists who co-authored this paper, to lead the studies in the lab, and working on identifying and characterizing those genes,” he explains.

“Post-menopausal women would go to the doctor because of bleeding, and they would get a biopsy of their uterus and the biopsy was benign, and then sometime down the road they developed endometrial cancer.”

Dr. Mariani

Dr. Mariani says fortunately, most women are diagnosed with an early stage of endometrial cancer.

“Why? Because many are post-menopausal patients who start to bleed, and so they seek the attention of the doctor. They get scared,” Dr. Mariani says.

But not all outcomes are favorable, he adds. Nearly 20 percent of patients are diagnosed with an aggressive form of the cancer.

“Studying this group of patients is the most important in studying endometrial cancer,” he says. “We are focusing on treating these patients, but also, we are studying how to prevent this cancer,” he says.

Two biomarkers may help identify endometrial cancer risk

The study comes on the heels of a previously published endometrial cancer study by Dr. Walther-Antonio and Dr. Mariani, which identifies a reproductive tract microbiome signature promoted in part by post menopause. 

“With results from these two studies, we will look at the two biomarkers — the microbiome and epigenetic — to see if these are connected or just happen to both be biomarkers in cancer,” she says. “We think the microbiome is probably the driver, but it could very well be the other way around too. We just don’t know.”

Dr. Mariani says obesity is another known factor.

“This may represent an opportunity to prevent the development of endometrial cancer altogether.” – Dr. Walther-Antonio

“The reason for that is obesity creates in women a very high estrogen environment, and this stimulates the uterine lining, and so this is a very high risk factor for endometrial cancer,” Dr. Mariani says. 

Dr. Mariani and Dr. Walther-Antonio plan to expand their studies on microbiome and methylation, in a larger group of patients with aggressive endometrial cancer. 

By identifying molecular markers of the disease, an effective tool could be developed to predict which patients are at high risk of developing endometrial cancer, Dr. Walther-Antonio says.

“More importantly, these markers could also be targeted for primary prevention during the window of time between a benign biopsy that contains altered markers and the development of the disease,” she says. “This may represent an opportunity to prevent the development of endometrial cancer altogether.”

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This article was originally published on the Individualizing Medicine blog.

Tue, Mar 24 6:00am · Individualized care for psychiatric disorders -- Mayo Clinic Biobank + genetic testing could pave the way

By Sharon Rosen

Joanna Biernacka, Ph.D.

Patients suffering from depression, anxiety and substance use disorders often search for years to find treatment. Studies have shown that during this time gap, patients’ symptoms worsen, increasing their risk for other chronic illnesses, shortened lifespan and poor quality of life.

Mayo Clinic statistical geneticist Joanna Biernacka, Ph.D. and her colleagues are working to change that equation, using electronic health records and genetic data from thousands of patients, including Mayo Clinic Biobank participants, to better understand the underlying causes of these disorders. Dr. Biernacka and her team hope to uncover genetic and clinical biomarkers that can help us predict who may be at risk for developing these disorders.

“There is a tremendous need for better prevention, faster diagnosis and more individualized treatments for patients who suffer from psychiatric disorders. It’s an exciting time to be searching for answers. We are making progress and now have new statistical and genetic models to help make discoveries that will advance care.”  

Joanna Biernacka, Ph.D.

“There is a tremendous need for better prevention, faster diagnosis and more individualized treatments for patients who suffer from psychiatric disorders. It’s an exciting time to be searching for answers. We are making progress and now have new statistical and genetic models to help make discoveries that will advance care,” says Dr. Biernacka.   

Developing a risk score to customize care

Working with colleagues in the Mayo Clinic Center for Individualized Medicine, Dr. Biernacka and her team will first be examining the electronic health records of 60,000 Mayo Clinic Biobank participants to identify clinical traits of these disorders.

“There is not just one type of depression – each form of the disease has different symptoms and levels of severity. The same is true for anxiety and substance use disorders. Because Mayo Clinic psychiatrists provide such in-depth clinical evaluations for patients with these disorders, we hope to identify key clinical traits for the many subtypes of disease,” she says.  

In the next stage of their research, investigators will analyze genetic test results for these same participants — an effort made possible through a research study known as Project Generation. The study is a collaboration between Mayo Clinic Center for Individualized Medicine and Regeneron Pharmaceuticals that will yield whole exome sequencing data on Mayo Clinic Biobank participants as well as additional Mayo Clinic participants.

“While diseases such as cancer, heart disease and diabetes are widely known to have genetic causes, we know that genetics also plays a key role in many psychiatric disorders. Having the genetic data for a large group of patients with these disorders will be a game changer. We’ll have a window into these diseases that we have been unable to open thus far,” says Dr. Biernacka.

“We hope the breadth and depth of information from analyzing larger patient populations will help us develop a polygenic (multiple gene) score that can be combined with social and environmental factors to predict who is at risk for developing these conditions. These scores could also speed diagnosis and identify the best treatments or treatment targets for individual patients.”

Dr. Biernacka

Researchers suspect there are hundreds or even thousands of genes that may be causing the different subtypes of these psychiatric disorders.

“We hope the breadth and depth of information from analyzing larger patient populations will help us develop a polygenic (multiple gene) score that can be combined with social and environmental factors to predict who is at risk for developing these conditions. These scores could also speed diagnosis and identify the best treatments or treatment targets for individual patients,” she says.

Dr. Biernacka and her Mayo colleagues, along with researchers from New York State Psychiatric Institute/Columbia University, Icahn School of Medicine at Mount Sinai, and Weill Cornell Medicine, were recently awarded a National Institutes of Health research grant on Polygenic Risk Score Modeling to Predict Psychiatric Disorders and Clinical Outcomes (related article) to support this research.

Finding answers, offering patients relief

For Dr. Biernacka, the potential to create this type of risk score is why she chose a career as a statistical geneticist.

“My role has combined my interests in biology and genetics, while allowing me to use my analytical skills to support medical research and ultimately improve care for patients,” she says.

Dr. Biernacka initially came to Mayo Clinic to support the Samuel C. Johnson Genomics of Addiction Program. She now serves as the director of Mayo Clinic’s Psychiatric Genomics and Pharmacogenomics Program and is the co-principal investigator, along with Mark Frye, M.D., for the Mayo Clinic Bipolar Disorder Biobank.

“Our team is committed to advancing individualized care for patients with psychiatric disorders. By reducing the time it takes to diagnose and treat patients, we hope to offer them relief from their symptoms, improving their overall health and quality of life.”

Dr. Biernacka

“Our team is committed to advancing individualized care for patients with psychiatric disorders. By reducing the time it takes to diagnose and treat patients, we hope to offer them relief from their symptoms, improving their overall health and quality of life.”

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This article was originally published on the Mayo Clinic Center for Individualized Medicine blog.

Tue, Feb 18 6:00am · Mayo researchers studying 'promising' new approach to treating advanced cancer, 1 patient at a time, 1 tumor at a time

George Vasmatzis, Ph.D., stands in a Mayo Clinic laboratory dedicated to the Ex Vivo study, which tailors the most effective drug, or drug combination, to each individual cancer tumor.

A collaborative team of Mayo Clinic scientists is studying an innovative strategy for treating advanced cancer, using genomics and human tumor samples as their guide. The novel approach, called Ex Vivo, creates a miniature cancer replica for testing therapies outside a patient’s body, combined with a comprehensive genomic analysis of a patient’s cancer cells.

“We are now at the cusp of understanding cancer at the individual level, the molecular complexity level, says George Vasmatzis, Ph.D., study leader and co-director of Mayo Clinic’s Biomarker Discovery Program within the Center for Individualized Medicine.

Dr. Vasmatzis says Ex Vivo ultimately tailors the most effective drug, or drug combination, to each individual cancer tumor. He envisions the study leading to a transformation in how patients with cancer are diagnosed and treated.

“We were blind and now we can see,” Dr. Vasmatzis says, “because if you can understand cancer, you can manage it.”

Reshaping precision medicine

More than 1.8 million people in the U.S. were diagnosed with cancer in 2019, according to the American Cancer Society, and an estimated 610,000 deaths were attributed to the disease. A majority of the cancer deaths were the result of metastases, when clusters of cancer cells circulate and spread to vital organs.

Panos Anastasiadis, Ph.D., studies cell-to-cell adhesion and cell interactions in cancer tumors at a Mayo Clinic laboratory. 

The Ex Vivo strategy centers on finding treatment options where none have existed, by knowing the full story of each tumor and recognizing every patient’s cancer as a unique disease of mutated cells.

A former electrical engineer who has dedicated his career to unlocking the mysteries of cancer, Dr. Vasmatzis says cancer can no longer be viewed as one disease, or even a dozen diseases.

“Because even within the same tumor, different cells can have different genetic changes,” he explains. “Cancer cells evolve and multiply, and when cancer becomes advanced it loses the connection of where it started from — the lung, breast, brain — and it becomes more individual. It is why drugs that are fully effective in some patients provide little or no response in others.” 

Ex Vivo in action

The Ex Vivo process starts with taking a small biopsy of a patient’s cancer tumor and dissecting the genetic details at high resolution to find out where the cancer is going and what it is doing. Dr. Vasmatzis says peeling away the many layers of complex information takes a team of highly specialized medical experts in oncology, pathology, biology, genetics and more.

“Our team is carefully constructed to run like an engine, and this is where it happens,” he says, walking through the laboratory, where clinicians and scientists are peering into microscopes, running high-tech machines and studying whole genome images on large computer screens.

“We are now at the cusp of understanding cancer at the individual level, the molecular complexity level.”

George Vasmatzis, Ph.D.

George Vasmatzis, Ph.D. (left) and Sotiris Sotiriou, M.D., look at images of DNA and RNA extracted from tumor cells, at a Mayo Clinic laboratory.

“For example, a very sophisticated tissue acquisition team is extremely important in making sure we are extracting the right cell types,” he explains. “We need molecular biology expertise to get billions of bits of data out of the cells and amplify that information for sequencing. Then, you need analytics people and mathematicians to be able to interpret and develop algorithms.”

Dr. Vasmatzis says, many times, the entire lab is focused on just one patient’s cancer.

“One person at a time, one tumor at a time,” he says.

Replicating cancer tumors

After uncovering the cancer’s genomic roadmap, the second part of the study begins with testing existing FDA-approved drugs on the cancer cells.

Overseeing the microcancer portion of the study and co-leading the project is Panos Anastasiadis, Ph.D., a cancer biologist and chair of the Mayo Clinic Department of Cancer Biology, with expertise in cell-to-cell adhesion and cell interactions in cancer tumors. 

Dr. Vasmatzis says early results of the first 100 Ex Vivo tests are “promising.”

“Ex Vivo enables us to stay ahead of the cancer instead of behind it,” he says. “This is the way forward for individualized medicine.” 

Dr. Anastasiadis and his team use a second piece of a patient’s tumor to create 3-D miniature cancer replicas.

Image of DNA

“We separate all the cells that formed that tumor,” he explains. “So whatever that tumor was, now it is individual cells.”

Then, small numbers of cells are divided into liquid droplets, where the cells regroup, he describes.

“The cells that were originally part of the tumor structure were adhering to each other,” he explains. “And they adhere to each other again in the 3-D cultures.”

Dr. Anastasiadis says the cells form miniature versions of the tumor that was originally inside the patient’s body.

“Only now it is outside of the patient’s body and we can test drugs on it,” he says. “And we’re looking for the drugs and drug combinations that target the genomic alterations in each patient’s individual tumor, and that will kill most, or all of the cells,” he explains. 

Each miniature cancer model can screen dozens of drug candidates, including combinations not tried before, as well as immunotherapies and viral therapies.

“Using advanced genomics, we usually identify quite a few, maybe 10 to 20 potential targets for treatment,” he says. “Microcancer screening identifies the most effective therapy outside the body. Our theory is that when we treat the patient with this therapy, we will also have a strong response to treatment.”

“Ex Vivo enables us to stay ahead of the cancer instead of behind it. This is the way forward for individualized medicine.” 

Panos Anastasiadis, Ph.D.

Strength in numbers

Dr. Anastasiadis emphasizes the strength of Ex Vivo is in doing both parts: the genomics and the miniature cancers. He says doing just one or the other only paints a portion of the picture.

“Through genomics, we know only certain mutations or amplifications, which we call ‘driver genes’ or ‘driver mutations,’” he says. “Knowing just the genomics is inconclusive. You need both.”

He points to the “HER2 protein” in breast cancer as a good example. Patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer, accounting for one in five breast cancer cases, are treated with HER2-targeted therapy, but it is not always effective.

“We don’t know why just 70% of patients respond to the HER2-targeted therapy while 30% do not,” he says.  “Complicating things, in most cases you have more than one potential driver, but you don’t know where to target therapy”.

Dr. Anastasiadis says that by testing a drug on the tumor before testing it in the patient can clear these uncertainties. He says Ex Vivo seeks to eliminate the trial and error of patients being exposed to drugs that are often toxic and provide no benefit.

“Ex Vivo is the paradigm we need. There are very few metastatic or advanced cancers for which available therapies provide meaningful longevity.”

Minetta Liu, M.D.

Minetta Liu, M.D.

From innovation to patient care

After the completion of each Ex Vivo test, researchers and clinicians gather for a comprehensive review, including Minetta Liu, M.D., a Mayo Clinic medical oncologist and research chair for the Department of Oncology. 

“Ex Vivo is the paradigm we need,” says Dr. Liu, whose clinical focus is on breast oncology.

Dr. Liu emphasizes the study is not designed to treat patients yet, but when it does translate to clinical care at Mayo Clinic, she believes it could be life-changing.

“There are very few metastatic or advanced cancers for which available therapies provide meaningful longevity,” Dr. Liu says. “Precision drug selection is clearly needed. This will be accomplished through genomics and functional modeling to gauge which therapies will work best for an individual at that particular point in their disease course.”

The Ex Vivo team plans to continue the study for one-to-two more years before bringing the procedure to the clinic.

“What I’m hoping is that as we gain knowledge, we will start seeing patterns that will work,” Dr. Vasmatzis says. “We have a lot of work to do to take the next step, but we are all passionate in bringing this to our patients in the near future.”

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This article was originally published on the Center for Individualized Medicine blog.

Thu, Jan 9 6:00am · In a first, researchers sequence single bacterial cells, paving path for rapid sepsis test

Dr. Liu is looking at a see-through rectangle with tiny circuitry running throughout, holding it in her gloved hands.
Mayo Clinic senior research fellow Yuguang Liu, Ph.D., looks into the microfluidic platform she developed for sequencing genomic contents of single bacterial cells.

For the first time, Mayo Clinic researchers are sequencing the genomic contents of single bacterial cells. The technique may pave the way for a potential lifesaving test for sepsis, a serious and sometimes deadly condition caused by the body’s response to an infection. Rather than waiting for days to identify the source of a patient’s infection, the new test could provide an answer in hours and help pinpoint an effective therapy.

“When you’re dealing with bacteria, it only takes a few resistant cells to give a patient a bad outcome,” says Marina Walther-Antonio, Ph.D., associate consultant in the department of Surgery, and assistant professor in the Mayo Clinic Center for Individualized Medicine Microbiome Program, with a joint appointment in the department of Obstetrics and Gynecology.

“In principle, the research will enable the identification of pathogens within a few hours, buying precious time in what is often a life threatening battle,” Dr. Walther-Antonio says.

Dr. Walther-Antonio is holding a large vial of fluid with a swab of it in her other hand.
Mayo Clinic researchers, Yuguang Liu, Ph.D. (left), and Marina Walther-Antonio Ph.D. (right), look at bacterial cells.

Rocketed to space

Mayo Clinic’s vast achievement of extracting DNA and RNA from single bacterial cells started as a study on the International Space Station as part of a large multidisciplinary team effort designated as BIOMEX (Biology and Mars Experiment), where three types of tiny microorganisms spent almost two years in orbit. Once back on Earth, Dr. Walther-Antonio, an astrobiologist who worked with NASA Astrobiology Institute during her training, set out to investigate whether the cells had mutated in order to survive in space, away from Earth’s protection. She believed the study would play a key role in understanding how to treat diseases in humans. 

The only thing missing was the tool needed to retrieve the genomic details that were locked tightly inside the cells. 

Dr. Walther-Antonio turned to Mayo Clinic senior research fellow Yuguang Liu, Ph.D., an electrical engineer from Shanghai, China, who received her Ph.D. in biological applications at the University of Cincinnati.

“Dr. Liu is one of the only engineers in the world with this kind of expertise,” Dr. Walther-Antonio says. 

Dr. Liu, an expert in microfluidic platforms, recalls when she eagerly accepted the challenge.

“I knew it had never been done before, but I came here to identify problems that needed to be solved,” she says.

gloved hand holding see-through rectangle (microfluidic platform) with wires connected to it in a number of spots. Microscope in scene
Yuguang Liu, Ph.D. connects a microfluidic platform to a machine to isolate and sequence single bacterial cells.

Bacterial cells, found in every habitat on Earth, are generally smaller than a pinhead, with a thick protective outer wall to enable survival in harsh environments, such as the human gut, bloodstream, soil and waters in extreme temperatures or under high radiation. Some bacterial cells help plants absorb nitrogen, others assist with human digestion. Many cause diseases. All can divide and multiply exponentially, with mutations occurring throughout the process. 

A unique tool

“Genomic sequencing has been done in human cells, but there is tremendous difficulty to do it in bacterial cells because they are very hard to break down without damaging the minute amount of DNA inside with methods compatible with downstream processing,” Dr. Liu explains.

Against great odds and in just months, Dr. Liu accomplished the unprecedented task by formulating a chemical-based “cocktail” to help break down the strong cell wall while keeping its fragile ingredients intact. She also made a special microfluidic platform — a credit card-sized piece of plastic with short, pin-like plastic spikes and raised lines that form a grid design for controlling and manipulating fluids. The chip contains nano-sized chambers for compartmentalizing single bacterial cells. 

“This tool can take the bacterial single cells and extract the DNA and RNA and amplify them and sequence them to see exactly what they are and what they are doing,” Dr. Liu explains, as she connects the chip to a machine with dozens of clear thin tubes that distribute gas pressure to operate the chip for isolating the cells and DNA/RNA amplification.

“We are now able to look at the genome to understand what drugs they are resistant to,” Dr. Liu explains.

Dr. Liu looking through eyepiece of large electronic microscope, holding the wired glass square (microfluidic platform) under the lense.
Yuguang Liu, Ph.D., looks at single bacterial cells through a microscope.

Dr. Walther-Antonio says she was amazed with how quickly Dr. Liu accomplished the task.

“She came to me with the results and said, ‘I think it kind of worked,’” Dr. Walther-Antonio recalls. “And I said, ‘Did you try it again?’ And she said, ‘Yes, 10 times.’”

Rapid sepsis diagnosis

Dr. Walther-Antonio says her team is now able to expand the technique to develop a real-time test for sepsis, which is often hard to diagnose and difficult to determine the most effective antibiotics to use on a patient. Without rapid treatment, sepsis can lead to septic shock, organ failure and death. In 2018, nearly 270,000 people in the U.S. died as a result of sepsis, according to the Centers for Disease Control. 

“The standard of care for sepsis currently involves culturing a patient’s blood sample and that always takes at least a couple of days,” she says. “In the meantime, you’re given a cocktail of antibiotics to try to save your life, and those who survive suffer lifelong side effects.”

Dr. Walther-Antonio envisions an automated process for identifying bacterial pathogens in sepsis within a few hours for time sensitive intervention, with an overall goal of saving lives.

gloved hand holding up clear palm-sized rectangle with gold circuitry visible throughout
Dr. Yuguang Liu holds up a microfluidic platform she designed for separating bacterial cells from human cells .

At the heart of the project, called “Answers in Hours,” is another microfluidic platform made by Dr. Liu — this one will separate human cells from bacterial cells.

“In a blood sample, there are very low amounts of bacteria,” Dr. Liu says. “Most are human cells, which overwhelmingly hide the bacterial cells. So in this platform, we have a measure to remove the human component so we are only detecting the bacteria.”

Dr. Walther-Antonio says knowing the genomic makeup of a tiny single bacterial cell opens the door to a world of discoveries, such as detecting the recurrence of pathogens early, and for basic science to understand what promotes the emergence of resistant strains.

She says research of patient sample testing is estimated to start in 2020, with plans to eventually incorporate the test into a clinical setting if success is reached.

The project was originally conceptualized by Heidi Nelson, M.D., and is also led by Nicholas Chia, Ph.D., Bernard and Edith Waterman co-director for the Mayo Clinic Center for Individualized Medicine Microbiome Program, and Robin Patel, M.D., chair of the Division of Clinical Microbiology and director of the Infectious Diseases Research Laboratory.

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