ROCHESTER, Minn. — Researchers in a Mayo Clinic-led study have shown how to detect a broad range of DNA mutations in noncancerous human tissues and across the genome. The analysis, drawing on more than 90 trillion DNA letters of sequencing data, could help scientists study when these changes arise — from early development through aging — and how they contribute to cancer and other diseases. 

Published in Cell, the study is the flagship paper in a package of roughly a dozen publications from the National Institutes of Health (NIH) Common Fund's Somatic Mosaicism across Human Tissues, or SMaHT, Network. The network includes more than 300 members from more than two dozen U.S. universities and hospitals. Researchers evaluated approaches for detecting somatic mutations ranging from single-letter DNA changes to large deletions, insertions and rearrangements. 

Alexej Abyzov, Ph.D., a Mayo Clinic professor of biomedical informatics who leads the Somatic Mutations in Development and Aging Laboratory, is the corresponding author of the Cell study. 

Reading the cellular mosaic

Unlike inherited genetic changes, somatic mutations arise after conception and accumulate over a lifetime. As cells divide, they can pass those changes to new cells, creating genetic differences within the same person, known as somatic mosaicism. Some somatic mutations can alter how cells behave and contribute to cancer, aging, and neurodevelopmental, cardiovascular and autoimmune diseases. 

These mutations can be difficult to detect when they are rare or occur in complex, repetitive regions of the genome. The SMaHT Network compared short- and long-read whole-genome sequencing, duplex sequencing, single-cell sequencing, and computational approaches. 

One of the clearest findings came from long-read sequencing, which reads longer stretches of DNA at a time. Much like reading a full sentence instead of a few scattered words, the added context made large genetic changes easier to find. Long-read sequencing detected about twice as many large DNA changes as short-read sequencing. It also found insertions that shorter reads often missed. 

Researchers improved detection in other hard-to-read parts of the genome too. In one benchmark, a more complete genome reference raised precision from 79% to 89%. Single-cell sequencing of 102 lung and colon cells revealed differences from cell to cell and helped trace their history back to early development. 

Companion study maps rare mutations across tissues

Dr. Abyzov also co-led a companion SMaHT paper published in The American Journal of Human Genetics. Deep whole-genome sequencing accurately detected rare, single-letter DNA changes present at levels below 1% in a tissue sample. 

Analyzing DNA from different organs also helped detect mutations that arose early in development and spread to multiple tissues. Combining lung and colon data uncovered 13 additional shared mutations, improving detection by 145% for these very rare mutations compared with analyzing either tissue alone. 

SMaHT aims to catalog somatic mutations across 10 to 15 tissue types from 150 donors while improving the tools used to detect them. NIH is planning a second stage focused on understanding how these mutations influence biological processes and disease. 

Dr. Abyzov says the research could eventually help identify people at higher cancer risk and track precancerous changes in tissues before developing symptoms.  

The studies were supported by the NIH Common Fund through the Office of Strategic Coordination in the NIH Office of the Director. The companion study received additional NIH support for work conducted at Mayo Clinic. For complete author lists, disclosures and funding information, review the Cell study and the companion The American Journal of Human Genetics study. 

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About Mayo Clinic   
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.   

Media contact:    

• Julie Ferris-Tillman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu 

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On a cold December night more than a decade ago, a snowmobile crash on a rural Iowa road left Chad Rockow with a shattered lower leg — and months of surgeries, setbacks and pain so severe he considered amputation.

Nearly 13 years later, he learned the accident had set something else in motion: a Mayo Clinic discovery of a hidden, inherited disease affecting his entire family.

"At the time, the accident felt like the worst thing that could happen," Chad says. "My career, my life, everything turned upside down. But now I see it as the best thing because it may have saved my life, my sister's life, my brother's life and my dad's."

Watch: Chad's story | Videography by Kevin Sullivan, Mayo Clinic

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The reason for the phone call traces back to Chad's recovery. When his leg failed to heal properly, Chad came to Mayo Clinic for specialized care. During treatment, he enrolled in the Mayo Clinic Biobank, donating a blood sample and joining tens of thousands of volunteers helping researchers unlock the genetic roots of disease.

His leg eventually healed, and Chad returned to life on his Iowa farm, rarely thinking about the blood sample he had left behind.

A life-changing phone call

Nearly 13 years later, his phone rang.

On the line was a Mayo Clinic genetic counselor. Researchers had identified a rare inherited mutation in a gene called SDHD. The mutation is linked to paraganglioma-pheochromocytoma syndrome, a condition that can cause tumors to form, often without symptoms.

Some remain slow-growing for years. Others can become life-threatening if not caught early.

"I remember thinking, 'This can't be me,'" Chad says. "I had zero symptoms."

But as the counselor explained how the mutation is passed down, pieces of his family's history began falling into place.

Years earlier, his father had undergone surgery to remove tumors from his neck. Other relatives had faced similar diagnoses. One had suffered a devastating stroke after a tumor wrapped around a carotid artery.

Chad added his father to the call and gave permission to review decades-old medical records. There it was, buried in surgical notes: paraganglioma tumors.

"That's when the hair stood up on the back of my neck," Chad says. "Everything connected."

Follow-up clinical genetic testing confirmed the mutation across the family. His father tested positive first. Then Chad. Then his brother and sister — none of whom had any symptoms.

Targeted imaging revealed that the mutation had already left its mark on all four of them. Chad had three tumors in his neck, including one wrapped around a carotid artery.

His father's tumors have returned decades after his original surgeries. His sister has two tumors in her neck. His brother faces the most advanced disease, with multiple tumors, including a cancerous tumor near the skull and spine.

Chad and his brother have since undergone surgery at Mayo Clinic, with additional surgery planned for his brother. His father continues treatment there, and all four family members remain under specialized surveillance.

From biospecimens to breakthroughs

When the Mayo Clinic Biobank began enrolling volunteers in 2009, the sequencing technologies that would one day reveal Chad's mutation didn't yet exist.

"We never would have dreamed this was possible at that time to do the kind of research that we can do now," says Dr. Janet Olson, an epidemiologist who helped build the Mayo Clinic Biobank and now serves as its principal investigator.

"It took years to recruit the patients, collect the samples, extract the DNA and build the infrastructure," Dr. Olson says. Now we're getting back those gold nuggets, and Chad's story is a great example of one of those gold nuggets.”

What started as a research resource — linking blood samples, DNA and health data from thousands of volunteers — has become a powerful engine for discovery, supporting more than 500 studies.

Each sample contains layers of information such as DNA, serum, plasma and white blood cells, offering different windows into human health. Over time, when linked with medical records, these samples evolve into a powerful resource, enabling deeper understanding of disease, identifying risk and accelerating discovery.

One of the Biobank's most ambitious efforts focused on the DNA contained within those samples. Mayo Clinic Biobank Project Generation analyzed genetic data from more than 52,000 participants, searching for variants tied to 78 medically actionable conditions, including cancers and cardiovascular diseases where early detection can change outcomes.

The project ultimately identified Chad's mutation and has offered results to nearly 1,000 participants whose findings could directly affect their health.

A gold mine of discovery

Dr. Olson describes the Biobank as a "gold mine" built through years of scientific investment — and patient trust.

"It took years to recruit the patients, collect the samples, extract the DNA and build the infrastructure," Dr. Olson says. "Now we're getting back those gold nuggets, and Chad's story is a great example of one of those gold nuggets.”

Chad's story illustrates the vision behind Precure Research, Mayo Clinic's initiative to identify disease before symptoms appear and intervene earlier, when treatment has the greatest chance to change outcomes.

For Chad, the mutation may always be part of his family's story, but he hopes it will no longer define their future. For the first time in generations, his family can see it coming.

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When part of the liver is removed to treat cancer or other conditions, the remaining tissue must regenerate to restore liver function.  

In this Mayo Clinic Minute, Dr. Patrick Starlinger, a hepatobiliary and pancreas surgeon at Mayo Clinic Comprehensive Cancer Center, discusses research to help the liver regenerate after surgery. 

Watch: The Mayo Clinic Minute

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How does the liver regenerate after surgery?

"The liver can regenerate quite dramatically, probably the most potential to regenerate in the entire human body, and we leverage this in liver surgery," says Dr. Starlinger.  

Before surgery, the team measures liver volume and assesses liver function to determine how much can be safely removed to take out the tumor while leaving enough healthy liver to regenerate.  

But in some patients, that regeneration does not happen, which can lead to liver failure and limit which tumors can be removed.  

"Our area of research is so important to understand the mechanism of liver regeneration in humans, particularly because as we understand the mechanism, we can move forward with interventions to promote regeneration in these patients," says Dr. Starlinger.  

What role does blood clotting play in liver regeneration?

Mayo Clinic researchers have analyzed liver samples from patients with healthy livers and those with underlying liver conditions to better understand what drives regeneration.   

"We were able to discover that the blood coagulation system is crucially important to allow these mechanisms of liver regeneration to actually occur," says Dr. Starlinger.     

More research is needed, but researchers hope these findings could eventually lead to treatments that promote liver regeneration and expand the limits of liver surgery.

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Mayo Clinic scientists are pushing medicine beyond diagnosis, developing treatments for ultrarare genetic diseases while building a model that could accelerate the path to treatment for many more. 

Behind the glass walls of her Mayo Clinic neuroscience laboratory, Margot Cousin, Ph.D., watches tiny clusters of living neurons flicker across her computer screen. Magnified hundreds of times, the cells carry the genetic variant responsible for KCNK9 imprinting syndrome, one of the rarest neurological diseases in the world.

Dr. Cousin directs Mayo Clinic's N-of-1 Therapeutics Program, where scientists develop treatment strategies for diseases so rare they may affect only a single person. Each advance can help shorten the path for the next ultrarare disease, and the one after that.

"For decades, the greatest success we could offer many patients was finally putting a name to their disease," says Dr. Cousin, a clinical and translational scientist in Mayo Clinic's Center for Individualized Medicine. "A diagnosis is an extraordinary achievement, but it's no longer the end of the journey. The future of medicine is turning that diagnosis into a path toward treatment."

Watch: One patient at a time, Mayo Clinic takes on the world's rarest diseases

Videography by Kevin Sullivan, Mayo Clinic

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The neurons glowing on Dr. Cousin’s screen came from a small skin sample donated by Summer Nagele, a 21-year-old from Illinois living with KCNK9 imprinting syndrome. Low muscle tone affects her movement, speech and eating. She has reduced lung function, tires easily, sometimes uses a wheelchair for longer distances, and underwent spinal fusion for severe scoliosis at 13.

Yet Summer has built her life around the very things the disease makes difficult. She sings the national anthem before cheering crowds, performs in musical theater, competes in eight Special Olympics sports — gymnastics is her favorite — and advocates for people with disabilities.

Another part of Summer's story is unfolding somewhere far quieter — under Dr. Cousin's microscope.

Fewer than 100 people worldwide are known to have KCNK9 imprinting syndrome. Many are children.

Dr. Cousin knows them by name.

A path beyond diagnosis 

For ultrarare diseases, the path to treatment is especially difficult. There may be only a handful of patients to study, little clinical evidence to guide trials and almost no commercial incentive to develop a therapy.

Dr. Cousin and her collaborators are using advances in genetics, disease modeling, molecular therapeutics and artificial intelligence to find another way.

Every potential treatment begins with a small sample of cells donated by the people Dr. Cousin and her team hope to help.

In the laboratory, researchers coax skin cells backward into stem cells and forward into the types of neurons affected by the disease. As the neurons begin communicating, the effects of the mutation come into view — a gene that is too active or a protein that doesn't function as it should.

Those living cultures also become a testing ground. Along the lab bench, Dr. Cousin and her team use precision pipettes to introduce potential therapies into tiny wells of neurons, then watch how the cells respond. Some are existing FDA-approved drugs being tested for a new purpose. Others are experimental genetic therapies developed specifically for the disease.

Turning discovery into a treatment strategy 

What began as an effort to understand KCNK9 imprinting syndrome is now evolving into an international push to develop the disorder's first treatment. 

In 2022, Dr. Cousin and her team identified 15 previously unknown genetic changes that cause the disease. Those discoveries provided definitive diagnoses for 21 families and established a stronger scientific foundation for understanding the condition.  

Earlier this year, the team launched a natural history study to follow people with KCNK9 imprinting syndrome over time and better understand how the disease progresses. That information could help researchers identify measures for future clinical trials and determine whether a potential treatment is making a difference. 

In the laboratory, the team is investigating antisense oligonucleotides as one possible treatment strategy. The molecules can be designed to alter how genetic instructions are carried out inside cells. Researchers are still working to better understand the mechanisms driving KCNK9 imprinting syndrome and developing cell models needed to test potential therapies. 

Families are helping drive that momentum. Among them are Melissa and Sean Kelley, whose 12-year-old son, Preston, has one of the most severe forms of KCNK9 imprinting syndrome. He communicates through an eye-gaze device and relies on a wheelchair. The Kelleys founded the KCNK9 Foundation, helping transform a small group of isolated families into a global research community. 

"We share a special bond that no one else really understands," Melissa says. "For all of us with kids who are affected, our hope is to see a therapy in our lifetime." 

That community recently came together in Dallas, where Dr. Cousin joined families, clinicians and researchers from around the world for the third Global KCNK9 Imprinting Syndrome Symposium. For one of the world's rarest disorders, bringing so many families into one room was a milestone in itself. 

Sean says those face-to-face encounters give researchers "a much more nuanced view" of the disease and the many ways it can affect patients.  

Summer and her parents were part of the group that traveled to Dallas. "We trust Dr. Cousin," says her mother, Autumn Nagele. "When Summer was invited to be a part of the research, we knew her participation would be meaningful." Her father, Michael Nagele, puts their relationship with Dr. Cousin more simply: "She's family now." 

Summer's thoughts are on the younger children with KCNK9 imprinting syndrome. 

"I want the younger kids to be able not to go through the stuff that I do," Summer says. 

Scaling hope for ultrarare diseases

The search for a KCNK9 treatment is one part of a much larger effort. Across other ultrarare diseases, Dr. Cousin and her collaborators are applying the same approach, and in some cases, have already carried it from laboratory research to experimental treatment.

In 2025, they helped deliver the first custom experimental genetic treatments for Autosomal Dominant Leukodystrophy (ADLD) to a Mayo Clinic patient. The rare, fatal neurological disease slowly destroys the brain's white matter, disrupting the pathways that allow different regions of the brain to communicate.

Dr. Cousin and her collaborators have since built a comprehensive ADLD program, bringing together an international disease study and a dedicated ADLD Clinical Care Center to better understand the disorder, expand access to expert care and prepare for future treatment trials.

One by one 

For Dr. Cousin, the significance of the work is measured in much more than data points on a screen.

That became especially clear during Summer's skin biopsy.

With Dr. Cousin beside her, Summer began naming all the other children she had met through the KCNK9 community. One by one, she called them out, as if bringing them into the room with her.

"I thought of all the kids that I'm helping," Summer says.

Some breakthroughs are measured in millions of lives. In Dr. Cousin's laboratory, they begin with one.

The Bigger Picture

The work aligns with Mayo Clinic Research's Clinical Impact initiative, which is accelerating the path from scientific discovery to clinical trials and patient care. For ultrarare diseases, that means creating a more direct route from understanding the biology of a disorder to developing and testing potential therapies.

The Beyond the Breakthrough special series goes inside Mayo Clinic research to meet the people advancing medicine and cures for patients.

For more stories like this, visit Beyond the Breakthrough. 

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Landmark ATOMIC trial brings immunotherapy to patients being treated with the goal of cure

ROCHESTER, Minn. — The Food and Drug Administration (FDA) has approved the immunotherapy drug atezolizumab in combination with chemotherapy for some patients with stage 3 colon cancer following surgery. The treatment is for patients whose tumors have deficient DNA mismatch repair, or dMMR.

The approval is based on results from the ATOMIC clinical trial led by Mayo Clinic. The study found that adding atezolizumab to standard chemotherapy reduced the risk of cancer recurrence or death by 50% compared with chemotherapy alone. FDA approval further establishes the addition of immunotherapy to chemotherapy as a standard treatment option in the curative setting and helps to make it more readily accessible to patients who may benefit.

"This approval represents a major advance for patients with a subset of stage 3 colon cancer," says Frank Sinicrope, M.D., a Mayo Clinic oncologist and leader of the ATOMIC study. "ATOMIC is the first study to show the benefit of immunotherapy after surgical resection in patients with locally advanced colon cancer with dMMR. The goal after surgery is to eliminate remaining microscopic cancer cells responsible for recurrence and thereby increase the number of patients who are cured of their disease."

The phase 3 ATOMIC trial enrolled 712 patients with stage 3 dMMR colon cancer that had been surgically removed and spread to regional lymph nodes. Patients were randomly assigned to receive standard chemotherapy alone or chemotherapy combined with atezolizumab, an immune checkpoint inhibitor, followed by additional atezolizumab.

At three years, 86.3% of patients who received immunotherapy plus chemotherapy were alive and free of disease, compared with 76.2% of patients who received chemotherapy alone. The findings were published this year in The New England Journal of Medicine.

Moving immunotherapy earlier in treatment

Immune checkpoint inhibitors have transformed the treatment for several advanced cancers. In colon cancer, they have been particularly effective against tumors with dMMR. These tumors have a defect in their ability to properly repair errors in their DNA during cell division, leading to the accumulation of multiple mutations that can make the cells more recognizable to the immune system.

Before the ATOMIC trial, immunotherapy was used primarily for advanced or metastatic dMMR colorectal cancer. ATOMIC examined whether activating the immune system after surgery that is intended to cure the patient could prevent cancer from returning.

"Instead of waiting until a patient's colon cancer has returned or spread, we can now use immunotherapy earlier when patients have undergone surgery and are able to prevent or markedly reduce the chance of recurrence," Dr. Sinicrope says.

Approximately 15% of colon cancers have dMMR. Testing a patient's tumor can identify dMMR and help determine the optimal treatment.

An important advance for younger patients

The approval also comes as colorectal cancer rates among younger adults continue to rise. More than one-quarter of patients enrolled in ATOMIC were younger than 50.

The trial included patients with Lynch syndrome, the most common inherited cause of colorectal cancer and the most common hereditary cancer syndrome. People with Lynch syndrome have an increased risk of developing several cancers, particularly colorectal cancer, and frequently develop cancer at younger ages. Colon cancers associated with Lynch syndrome generally have dMMR.

"For patients who develop colon cancer at a young age, preventing recurrence can translate into decades of life gained," Dr. Sinicrope says. "Being able to offer an effective treatment such as immunotherapy to improve the survival of these patients is especially meaningful for them and their families."

From scientific insight to a new treatment

ATOMIC grew from years of research into the biology of dMMR colon cancer. Dr. Sinicrope and colleagues previously observed that these tumors contain large numbers of inflammatory and immune cells, including those cells targeted by immune checkpoint inhibitors. Those findings provided the scientific rationale for testing whether immunotherapy could strengthen the body's immune response against cancer cells that can remain after surgery.

Dr. Sinicrope developed the study, which was conducted through the Alliance for Clinical Trials in Oncology, part of the National Cancer Institute-supported National Clinical Trials Network. Patients from the U.S. and Germany participated.

"The patients who participated in ATOMIC made this advance possible, and their contribution will change how we treat patients with dMMR colon cancer here and around the world," says Dr. Sinicrope.

The National Comprehensive Cancer Network previously updated its guidelines to include atezolizumab plus chemotherapy as a treatment option based on the ATOMIC findings. FDA approval establishes the regimen as an approved treatment for eligible patients in the U.S.

The National Cancer Institute of the National Institutes of Health and Genentech funded the ATOMIC study. See the study in The New England Journal of Medicine for a complete list of authors, disclosures and funding.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Julie Ferris-Tillman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu

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This aggressive brain cancer can extend beyond what's visible on a standard MRI, making it difficult to precisely target treatment. Just 5% to 7% of patients survive five years after diagnosis. 

Mayo Clinic researchers are studying advanced imaging techniques designed to bring more of the tumor into view and potentially give care teams a better-defined target. 

"We're trying to develop and improve treatments that will help extend the length of time patients live, as well as their quality of life and function while they're alive," says Dr. William Breen, a radiation oncologist at Mayo Clinic. "From a radiation perspective, we need to be able to accurately see the tumor to accurately target it and treat it as well as possible." 

Watch: The Mayo Clinic Minute

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Seeing tumors more clearly 

A standard MRI with contrast shows doctors where glioblastoma appears to be, but tumor cells can extend into the surrounding brain beyond what is clearly visible. 

"In over half of patients, we find a tumor more than a centimeter beyond the standard MRI-defined tumor, and in 20% of patients, we find a tumor more than 2 centimeters beyond the standard MRI-identified tumor," Dr. Breen says. 

To see more, Mayo Clinic investigators are combining advanced MRI techniques with research PET scans. The scans provide different clues, such as areas where cells are especially dense, where blood flow is increased or where there may be more aggressive tumor activity. 

Together, they can give doctors a more detailed picture of the tumor and where it may extend. 

Treating tumors more precisely and effectively 

Because glioblastoma can extend beyond what doctors see on a traditional MRI, radiation treatment generally includes an extra margin around the visible tumor to help cover cancer cells that may be hidden. 

Advanced imaging could help doctors more accurately identify those areas and tailor radiation accordingly. For some patients, that could mean treating a smaller area of the brain and reducing radiation exposure to healthy tissue. 

"By using advanced imaging, we're able to treat a smaller area in many patients and reduce the amount of normal brain receiving radiation, which may make for a safer and better treatment," Dr. Breen says. 

Researchers also are studying whether they can direct more intensive treatment toward areas that advanced imaging identifies as particularly concerning. 

Greater precision may make it possible to give a higher dose of radiation at each treatment and finish therapy sooner. Dr. Breen says treatment has been shortened from three to six weeks to one to two weeks for some patients, meaning fewer trips to the hospital and more time at home. 

Bringing specialties together 

The research brings together experts across Mayo Clinic, including neurosurgeons, radiation oncologists, neuro-oncologists, neuroradiologists and nuclear medicine specialists. 

"I think our strength at Mayo Clinic for treating glioblastoma is the multidisciplinary team," Dr. Breen says. 

While glioblastoma remains challenging to treat, advances in imaging, surgery, radiation, chemotherapy and other therapies are helping researchers continue to improve care. 

"We know there's still much progress to be made," Dr. Breen says, "but we have seen progress over the years to improve both quality of life and quantity of life for our patients with glioblastomas."

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Long before he set foot in a research lab, Alan Alwakeel was already asking big questions about medicine, technology and how to bring the two together. By the time he entered Mayo Clinic's SPARK (Science Program for the Advancement of Research Knowledge) program as a high school junior in the summer of 2024, he also was no stranger to experimenting with artificial intelligence (AI). 

Within two years, the project he began through SPARK had advanced well beyond the scope of a typical high school research experience, opening new opportunities for scientific exploration. 

SPARK is Mayo Clinic in Florida's research mentorship program that places high school students inside working laboratories on the campus. Scholars are matched with physician-scientists and researchers to design and carry out their projects while building research, critical thinking and professional skills. 

Instead of joining an existing project as most SPARK participants do, Alan arrived with a concept that captured the attention of Mayo Clinic's research faculty. He wanted to find a better way to identify effective cancer treatments, combining his interests in medicine and computer science. 

That idea would become the foundation of a project that moved far beyond a typical high school research experience. 

Building a 'virtual cell' 

As a SPARK scholar, Alan began developing an AI-powered "virtual cell" — a computational model designed to simulate how cancer cells respond to different drug combinations. He worked under the mentorship of Cui Tao, Ph.D., chair of Artificial Intelligence and Informatics Research. 

The problem Alan set out to solve is well known. Testing drug combinations in the lab takes time. With thousands of potential combinations, identifying the most effective treatments requires a highly systematic approach. 

Alan's approach aimed to shift that process into a more automated one.  

"My goal was to create a simulation that could predict how cancer cells would respond to different therapies, allowing researchers to test hundreds of thousands of drug combinations virtually before validating the most promising ones in the lab," he says.  

His model integrates genomic and proteomic data, running large-scale biochemical simulations to predict whether drugs will work together or interfere with one another. After building the system, Alan validated it through laboratory experiments, demonstrating strong agreement between the model's predictions and real-world outcomes.  

From project to discovery 

As his project gained traction, Alan connected with multiple Mayo Clinic scientists, including John A. Copland III, Ph.D., whose lab supported the work to validate the performance of the virtual cell. Dr. Copland quickly recognized that Alan and his work stood out. 

"He's done more than most people have done through a postdoctoral fellowship," says Dr. Copland.  

 As results began to take shape, the potential of the virtual cell became clear. After presenting validation data and demonstrating the model's accuracy, Alan and his mentors began exploring additional opportunities to refine the model and evaluate its broader research applications. 

The project marked a turning point. What began as a student-led research idea had evolved into a sophisticated technology with promising real-world implications for cancer research and drug discovery. 

Today, the team continues to assess how the model could be further developed and applied to support future scientific investigation. 

SPARK is designed to immerse students in the realities of scientific work, which can include uncertainty, skepticism and high expectations. From the outset, Alan's mentors challenged him to prove that his idea was feasible. Rather than simplifying the project, they asked him to build the case for it himself. 

"They didn't hold my hand through it," he says. "They encouraged me to do all of the research myself and defend the project." 

Learning to think like a scientist 

SPARK students are treated as colleagues, not observers, and Alan embraced that role fully.  

Rather than directing each step, Dr. Copland and his colleagues provided access to lab space, tools and expertise, allowing Alan to execute his vision. He worked across departments, integrating AI with laboratory science to create a project that spanned multiple disciplines. 

That process required him to teach himself advanced concepts in biochemistry and computational modeling, then explain and defend those ideas in front of experienced researchers. It also meant learning how to communicate professionally, work with principal investigators and navigate the demands of a real research environment.  

By the end of his senior year, Alan had accomplished things few students at any level achieve: a groundbreaking innovation, second-place Grand Award at the International Science and Engineering Fair, valedictorian at Stanton College Preparatory School and acceptance to Harvard University, where he plans to study neuroscience and computer science. 

He intends to continue working with his Mayo Clinic mentors to explore future applications of the virtual cell while pursuing his goal of becoming a physician-scientist. His work remains grounded in the belief that technology should support clinicians and improve the efficiency of care. 

"AI allows us to test possibilities at a scale that would be impossible in a traditional laboratory. It helps us focus resources on the solutions most likely to help patients," he says.  

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JACKSONVILLE, Fla. — Mayo Clinic researchers report encouraging early results from an experimental therapy targeting the genetic cause of a rare form of amyotrophic lateral sclerosis, or ALS. The study is published in Med. 

The single-patient study points to a broader possibility in precision medicine — using the genetic cause of a disease as a framework for testing highly targeted therapies, particularly for patients with rare conditions that have few treatment options. 

"I didn't think I would see this kind of research in my lifetime — identifying a disease-causing mutation, developing an experimental therapy and delivering it to a patient," says Björn Oskarsson, M.D., a Mayo Clinic neurologist and senior author of the study. "It speaks to the power of science and how far genetically targeted treatments have come." 

Targeting genetic ALS

That work builds on a long history of ALS genetics research at Mayo Clinic. In 2011, then-Mayo Clinic neurogeneticist Rosa Rademakers, Ph.D., and colleagues helped discover a mutation in the C9orf72 gene, now recognized as the most common inherited genetic cause of ALS. Dr. Rademakers received the 2026 Breakthrough Prize in Life Sciences for her role in the discovery. Mayo researchers also developed early models that helped scientists investigate how the mutation contributes to ALS.

Since joining Mayo, Dr. Oskarsson has helped translate advances in ALS genetics into treatment research, contributing to the first approved treatment of genetic ALS. 

ALS progressively damages motor neurons, the nerve cells that control voluntary movement. In this study, genetic testing identified a mutation in CHCHD10, a gene associated with a rare form of ALS. The mutation appears to make the CHCHD10 protein harmful to nerve cells and is linked to abnormal changes in TDP-43, a protein closely associated with ALS. 

Mayo researchers collaborated with the nonprofit n-Lorem Foundation, which develops medicines based on antisense oligonucleotides, or ASOs, for people with ultrarare genetic diseases. ASOs are short synthetic strands of genetic material designed to bind to RNA and reduce production of a protein that contributes to disease. The foundation developed and evaluated more than 320 ASOs targeting CHCHD10 before selecting a lead candidate based on specificity and early safety testing. 

Early signs of treatment response

The study reports on the patient's first six doses of the experimental ASO, delivered through injections into the fluid surrounding the spinal cord. Treatment was well tolerated, and levels of neurofilament light — a blood biomarker of nerve-cell injury — declined by as much as 50%. Measures of breathing, cognition and physical function remained stable or showed modest improvement. 

"The quick response in neurofilament light was very encouraging," Dr. Oskarsson says. In a progressive disease such as ALS, he adds, stabilization can be a meaningful observation. 

The study also gives researchers a chance to look more closely at what is happening inside cells during the therapy. Using samples collected before and during the delivery of the ASOs, the team is studying changes in TDP-43 as well as mitochondrial function and gene activity. The goal is to understand how suppressing CHCHD10 may affect the disease process at a molecular level. 

The therapy remains experimental research and is not standard clinical care. Dr. Oskarsson estimates that about 50% of ALS is genetic, but he notes that only a subset of those cases are currently suited to an antisense approach. Some genetic forms may require other strategies, including gene editing. 

A framework for precision

The study is part of a broader effort through Mayo Clinic's N-of-1 Therapeutics Program to learn which elements of drug development, clinical evaluation and monitoring can be applied across individualized genetic therapies. 

"Cases like this are how we get started," says Margot Cousin, Ph.D., director of the N-of-1 Therapeutics Program and lead author of the study. "They help us build the scientific, clinical, translational and regulatory framework to do this rigorously and equitably. As we learn how to scale these approaches, the impact could reach far beyond ultrarare disease." 

Research in ultrarare diseases can help establish safety benchmarks, refine genetic-treatment platforms and clarify which disease mechanisms are most amenable to targeted therapy. Those lessons could ultimately inform new approaches to more common diseases. 

For a complete list of authors, disclosures and funding, review the study. 

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About Mayo Clinic 
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.  

Media contact: 

• Tia Ford, Mayo Clinic Communications, newsbureau@mayo.edu 

The post Mayo Clinic researchers report early results from therapy designed for a single patient with rare genetic form of ALS  appeared first on Mayo Clinic News Network.

Mayo Clinic findings also link specific gut bacteria to cancer survival and identify a pretreatment signal associated with chemotherapy toxicity

ROCHESTER, Minn. — Mayo Clinic researchers have discovered distinct gut microbiome patterns in adults age 50 or younger with colorectal and breast cancers compared with those diagnosed later in life — one of several findings from an analysis of stool samples from 1,364 patients with cancer across cancer types, stages and treatments.

Among younger patients, those with colorectal cancer had higher lactate levels and more Veillonella parvula, a gut bacterium that feeds on lactate. Early-onset breast cancer showed changes across 64 bacterial species and lower levels of primary bile acids.

Published in Cell, the findings come from the Mayo Clinic Cancer Microbiome cohort, a real-world study that recruited cancer patients at Mayo Clinic in Arizona, Florida and Minnesota, representing 40 states. Stool samples were collected before patients began a new treatment regimen and linked to detailed clinical data on side effects and outcomes. The samples provided a window into the gut microbiome — the trillions of microbes living in the digestive tract.

Cancer-specific microbiome patterns emerge

Researchers first compared patients with cancer with 287 people without cancer to identify broad microbiome differences. Comparisons across cancer types then revealed more specific signals. After accounting for other health conditions, researchers pinpointed 341 bacterial species associated with five cancer groups.

Among those groups, neuroendocrine tumors showed a broad loss of common, health-associated gut bacteria. Liver and intrahepatic bile duct cancers had higher levels of several bacteria, including Enterococcus faecalis, while esophageal cancer had higher levels of six species, including several Streptococcus bacteria. Distinct associations were also found in lymphoid leukemia and multiple myeloma and related plasma cell cancers.

Distinct patterns in early-onset cancers 

The findings come as colorectal and breast cancer rates rise among younger adults. Colorectal cancer incidence is increasing about 3% a year among adults ages 20 to 49, while breast cancer incidence is rising 1.4% a year among women younger than 50, according to the American Cancer Society.

The colorectal finding raises questions about a possible biological connection: Tumors can produce high levels of lactate, which Veillonella parvula uses to grow. Whether that relationship plays a role in early-onset disease is not yet known.

In breast cancer, one of the 64 species that differed in younger patients was Clostridium scindens, a bacterium involved in bile acid and steroid metabolism.

No comparable age-related microbiome differences were found in brain cancer, the third cancer examined in the early-onset analysis. The colorectal and breast cancer findings do not establish that these microbial or metabolic differences cause early-onset disease, but they identify associations that warrant further study.

Gut microbiome linked to survival and treatment side effects 

Researchers also identified specific gut bacteria associated with survival in colorectal, liver and intrahepatic bile duct, melanoma, ovarian and prostate cancers. In liver and intrahepatic bile duct cancer, Bifidobacterium longum was associated with longer survival and Blautia A massiliensis with shorter survival.

Researchers also studied whether the gut microbiome before treatment was associated with diarrhea during chemotherapy, a side effect that can make treatment harder to tolerate. Among patients receiving 5-fluorouracil, or 5-FU, a chemotherapy used to treat many types of cancer, those who later developed diarrhea had lower levels of bacterial genes capable of breaking down the drug. Much of that function came from Anaerostipes hadrus, a common gut bacterium.

The same signal was not linked to diarrhea in patients receiving carboplatin, another chemotherapy drug, suggesting the finding was specific to 5-FU.

"The microbiome is not the sole driver of cancer or treatment outcomes, but it is an underappreciated component that has not traditionally been considered in therapeutic approaches," says senior author Purna Kashyap, M.B.B.S., a gastroenterologist, director of the Mayo Clinic Microbiome Program and Bernard and Edith Waterman Director, Microbiomics Program, Mayo Clinic Center for Individualized Medicine. "This gives us a proof of concept that we can begin to understand why some patients experience a particular side effect and identify a target that could potentially be acted upon."

Next, researchers will investigate whether cancer-specific microbial signals play a causal role in disease and validate the microbiome's potential to predict treatment side effects in larger patient groups.

The research was supported in part by the National Institutes of Health and philanthropic gifts from the Valhalla Foundation, the Maxine & Jack Zarrow Family Foundation, and other benefactors to the Mayo Clinic Microbiome Program and Center for Individualized Medicine.

Jun Chen, Ph.D., professor of biostatistics and consultant in Mayo Clinic’s Division of Computational Biology, is also a co-corresponding author. For a complete list of authors, disclosures and funding, review the study. 

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About Mayo Clinic  
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.  

Media contact:   

• Julie Ferris-Tillman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu 

The post Distinct gut microbiome patterns found in 5 cancer groups and in early-onset cancers appeared first on Mayo Clinic News Network.

ROCHESTER, Minn. — Mayo Clinic researchers led a multicenter study that found dividing radiation into several treatments, known as fractionated stereotactic radiosurgery, reduced the risk of cancer returning after surgery for brain metastases and was associated with improved survival compared with delivering radiation in a single treatment.

The findings are being presented today at the 2026 American Society for Radiation Oncology (ASTRO) Annual Meeting in Boston.

Brain metastases, also called metastatic brain tumors, are cancerous tumors that spread to the brain from elsewhere in the body. Radiation therapy is a standard treatment after surgery, but researchers note that about 30% to 40% of patients experience cancer recurrence at the surgical site despite treatment with single fraction radiosurgery.

"The study findings give us the evidence necessary to transform clinical practice. We can now offer patients a treatment that controls their disease and is associated with improved survival," says Paul D. Brown, M.D., radiation oncologist at Mayo Clinic Comprehensive Cancer Center and co-principal investigator of the study.  

Why dividing radiation may improve outcomes

Stereotactic radiosurgery uses 3D imaging to precisely deliver high doses of radiation while limiting exposure to surrounding healthy tissue. It is typically delivered in a single treatment and is commonly used to treat brain metastases.

"We see high recurrence rates in patients with brain metastases because the challenge is eliminating microscopic cancer cells left behind after surgery without exposing too much healthy brain tissue to high doses of radiation," says Dr. Brown.

Dividing radiation into multiple treatments allows clinicians to deliver a higher total dose. It also gives healthy tissue time to recover between treatments, while tumor cells do not have the same ability to repair.  

Previous retrospective studies have suggested that fractionated stereotactic radiosurgery is effective, but the approach had not been validated in a randomized clinical trial.

How researchers studied fractionated radiosurgery

The study enrolled 242 patients with one to four brain metastases. Each patient had at least one metastasis larger than 2 centimeters that had been surgically removed.

Patients were randomly assigned to receive either a single treatment of stereotactic radiosurgery or fractionated stereotactic radiosurgery delivered in three or five treatments. Radiation doses were based on the size of the treatment area. Brain metastases that had not been surgically removed were treated according to the same assigned schedule.

Researchers followed patients for a median of four years.

One year after treatment, 87% of patients who received fractionated stereotactic radiosurgery had no recurrence at the surgical site, compared with 81% of patients who received a single treatment. Fractionated radiosurgery also better controlled brain metastases that had not been surgically removed, although this result was not statistically significant.

Median overall survival was 29 months for patients who received fractionated stereotactic radiosurgery, compared with 20 months for patients who received a single treatment. Fractionated treatment was associated with a 31% lower risk of death.

"The survival benefit was an unexpected finding, and while the exact mechanism remains unclear, we suspect that advances in systemic therapies over the past decade may be interacting with better control of disease within the brain, and overall, better outcomes for patients," says Dr. Brown.

Researchers found no difference in side effects or complications between the two treatment approaches.

"This is a practice-changing clinical trial in our field, demonstrating that fractionated radiosurgery not only reduces recurrence after surgery for large brain metastases but may also improve overall survival," says Robert Mutter, M.D., chair of research in the Department of Radiation Oncology and co-leader of the Novel Therapeutics and Therapeutic Modalities Research Program at Mayo Clinic Comprehensive Cancer Center. 

For more information, funding and authors, read the ASTRO abstract.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

About Mayo Clinic Comprehensive Cancer Center
Designated as a comprehensive cancer center by the National Cancer Institute, Mayo Clinic Comprehensive Cancer Center is defining the cancer center of the future, focused on delivering the world's most exceptional patient-centered cancer care for everyone. At Mayo Clinic Comprehensive Cancer Center, a culture of innovation and collaboration is driving research breakthroughs in cancer detection, prevention and treatment to change lives.

Media contact:

• Julie Ferris-Tilman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu

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