Advancing the Science

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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4 days ago · Science needs to guide us, says Mayo Clinic's Dr. Gianrico Farrugia on "Face the Nation"

Dr. Farrugia stands with his arms folded over his chest.
Mayo Clinic President and CEO Gianrico Farrugia, M.D.

Mayo Clinic President and CEO Gianrico Farrugia, M.D., shared his perspective on next steps to address the COVID-19 pandemic on CBS News’ “Face the Nation” program that aired March 29, 2020.

In his interview with “Face the Nation” moderator Margaret Brennan, Dr. Farrugia said the focus needs to be on saving lives because “there is no direct end in sight,” and he emphasized that the multi-faceted approach has to be “driven by the science, not by conjecture.”

Dr. Farrugia also underscored that research and innovations that are happening across the country will improve the way health care providers test and track the outbreak on both macro and micro levels, to help flatten the curve of COVID-19 infections faster and help those in greatest need.

He praised health care workers and gave thanks for the heroic work they are doing around the clock to save lives and prevent further spread of the virus.

The full transcript of the interview can be found here. The latest news about COVID-19 from Mayo Clinic can be found here.


Fri, Mar 20 8:00am · Mayo Researchers Develop Unique Tool, Lab to Study Vaping

Vaping devices
Common e-cigarettes and vaping juices

Jon Ebbert, M.D., is sympathetic to the plight of the patients he sees who are struggling with addiction. “I saw a lot of addiction growing up,” he tells Rochester Magazine’s Steve Lange. “I know the damage it can do.”

Dr. Ebbert, a Community Internal Medicine physician and researcher in Mayo Clinic’s Nicotine Dependence Center, also understands why it can be so hard for his patients to stop using tobacco despite the negative effects the drug has on their bodies. “I understand that life is complicated. I understand that what drives drug addiction is the innate desire that we all have to escape pain and discomfort. I understand that we all need coping mechanisms,” he tells Rochester Magazine.

It’s that compassionate, firsthand understanding that’s driven Dr. Ebbert and fellow Mayo Clinic researcher Alexandra Ward to learn all they can about the chemical makeup of today’s ever-increasing and ever-changing vape solutions. The two also work to discover what patients are inhaling when they use cannabidiol (CBD) and tetrahydrocannabinol (THC) for the treatment of medical conditions — in hopes of figuring out, once and for all, if any are safe to inhale. “Half a million people die in this country every year from cigarettes,” he tells the magazine. “I’d love to find something safe to reduce that harm.”

And as the magazine reports, he and Ward are giving it all they’ve got. They’ve established their own Inhaled Particle Aerosol Lab within Mayo Clinic’s Nuclear Magnetic Resonance Spectroscopy lab to study the chemical make-up of vape, CBD and THC samples in a very unique, Star Wars-esque kind of way: By “force-feeding” today’s “next generation of drug delivery devices — e-cigs and vaping pens” into a literal “Cigarette Smoking Machine” (CSM) that looks and sounds like it would fit in a galaxy far, far away. “When it inhales — when the motor-driven pump sucks superheated vapor from the e-cig into a whistling-lips-sized hole in its faceplate — CSM makes an adorable electronic chirping sound, like R2D2 whenever he’s reunited with C3PO.”

Connection to COVID-19

Because it attacks the lungs, COVID-19 could be an especially serious threat to those who smoke tobacco or marijuana or who vape, says the National Institutes of Health.

More information is available on the National Institute on Drug Abuse website.

In addition, the Centers for Disease Control and Prevention have published special guidelines for people at risk of serious illness from COVID-19.

Mayo Clinic’s complete set of COVID-19 related news and information is housed in a central location online.

That’s a description that no doubt pleased Dr. Ebbert, as Lange notes the good doctor was wearing a pair of Yoda socks on the day of their interview. “We call her BB-Vape,” Dr. Ebbert tells the magazine of the Jedi Master Cigarette Smoking Machine.

While Dr. Ebbert would like to find a safe smoking alternative for his patients, what BB-Vape is showing time and time again is that vaping, in particular, remains particularly unsafe. “When you take an e-liquid, and put it in this device and heat it, you develop at least 18 new chemical compounds that didn’t exist in the e-liquid,” Dr. Ebbert tells Rochester Magazine. “This is a reaction vessel with new chemical species being created, including chemicals like formaldehyde, which can cause cancer. I can’t safely recommend any of these products to my patients right now. And I wish I could.”

Dr. Ebbert’s work with BB-vape and other addiction and tobacco cessation programs continues during the rising COVID-19 crisis. His sense of urgency is also rising because, “People who smoke or vape who already have compromised lungs,” he says, “may put them at increased risk for complications from COVID-19.” 

A version of this article was originally published on In the Loop.

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Thu, Mar 12 6:00am · How a childhood goal of advocating for the sick led to medical school and beyond

environmental photo of a smiling Dr. Gibreel standing next to a busy street

Unrealistic. Selfish. Impossible.

The words were lobbed at Waleed Gibreel, M.B.B.S., who has lived in the margins of two powerful forces that shaped him — his dream of becoming a top-flight surgeon and his reality of growing up in war-torn Sudan.

“I knew as a child that my ultimate goal was to be a doctor, no matter what it took,” Dr. Gibreel says. “I didn’t really have any understanding of what medicine was nor how to get into it.”

Dr. Gibreel’s dream and his accompanying reality led him from witnessing impoverished communities in Khartoum to becoming a meticulous and highly skilled pediatric surgeon. Along the way, he tended a gas station in Virginia, drove a cab and delivered pizzas on frigid Minnesota nights.

Watching, Waiting

The United Nations called the killing of 300,000 people and the displacement of 3 million more one of the worst humanitarian crises ever when Darfur, Sudan, exploded with civil war in the 2000s.

Although he was not directly affected by the war, Dr. Gibreel watched how the crisis shaped the country. People didn’t have access to medical care. Many died from a lack of basic necessities.

“When people are sick, they are vulnerable and need help. They need someone to be their advocate,” Dr. Gibreel says. “I wanted to be that person who could help someone when they truly needed it.”

Dr. Gibreel’s father was an accountant and his mother worked raising three children. But even professional workers had difficulty finding what is commonplace in the West — cohesive medical care and education.

Education is not free or compulsory in Sudan for children between ages 6 and 13. The literacy rate is 70%, and only half the population can afford to even attend school. Dr. Gibreel’s family strongly stressed the importance of education, and his father worked long hours just to ensure that the children would receive an education.

“I saw what my parents did for me, and I want to make sure I keep doing what I’m doing, so they can see me succeed and can be proud to know all their effort was worth it,” he says. “In Sudan, most teens have to get jobs to help their families. When I would tell someone about medical school and the additional five-plus years of training, they would say it’s not possible.

“They had to take care of their families. Putting my interests and dreams first was difficult for the community to understand, and some viewed it as selfish.”

But Dr. Gibreel pressed on, achieving and entering medical school at the British-founded University of Khartoum Medical School in Sudan, where his classes were taught in Arabic and English. He was drawn to anatomy and surgery because he liked being able to diagnose the cause of a patient’s condition and be able to act on it through surgery and immediately see the outcome.

In 2009, Dr. Gibreel graduated at the top of his 400-student class with a medical degree. After a yearlong internship, Dr. Gibreel knew he wanted more — to train with the best in the United States.

Sudan to the States

Sudan lacks many medical resources and opportunities. Consequently, doctors often work two or more jobs just to get by, medications are limited, and many areas are not safe.

With aspirations to train as an academic medical center surgeon, Dr. Gibreel embarked on his cross-continent voyage, landing in Arlington, Virginia, in 2011.

To join a medical practice in the United States as a foreign-trained physician can take up to 10 years because of the involved testing process, burdensome costs and often duplicative educational requirements. The biggest hurdle is gaining acceptance to a medical residency program, which requires obtaining medical experience in the U.S. prior to acceptance.

To get by, Dr. Gibreel spent his first year working numerous blue-collar jobs while studying for his medical exams.

Even so, he scored in the top percentile on his first medical exam.

Frequently asked about his accent, Dr. Gibreel would share his story about becoming a U.S. physician. A customer at the gas station he tended suggested he reach out to Sudan-born pediatric surgeon Abdalla Zarroug, M.D., who worked at Mayo Clinic at the time. A few days later, a friend referred Dr. Gibreel to the Sudanese American Medical Association, which also mentioned Dr. Zarroug.

“I called him and he was kind enough to allow me to come join him,” Dr. Gibreel says.

With that, Dr. Gibreel secured a one-year unpaid research position to gain the medical experience required to apply for residency.

To make ends meet, Dr. Gibreel drove a cab and delivered pizzas in Rochester for six hours each night after his days in the lab. What little downtime he had he spent studying for his medical exams to apply for resident positions.

Despite the long days and lack of sufficient study time and sleep, Dr. Gibreel once again excelled, and he was accepted into the Mayo Clinic General Surgery Residency Program at Mayo Clinic School of Graduate Medical Education.

The school is America’s first physician graduate program and one of the largest in the country. Learners at Mayo Clinic have extensive opportunities to conduct research, work beside experts in a clinical setting and receive tremendous career guidance and networking.

Mentors Mold the Man

Michael G. Sarr, M.D., Dr. Gibreel’s attending senior consultant in surgery at the time, recalls their first meeting while collaborating on a research project. “It was immediately obvious that Waleed was brilliant, despite his recent struggles to learn the language and social customs,” he says. “With his ever-present infectious smile and extreme intelligence, he won the heart and confidence of everyone he worked with.”

Extremely humble, Dr. Gibreel appreciates the mysteries of disease and the marvels of healing. He cites his advocates and mentors for his achievements and for helping him narrow his specialty to pediatric plastic surgery to restore function to kids born with congenital facial abnormalities.

Dr. Gibreel chatting with a young patient in an exam room.
Waleed Gibreel, M.B.B.S., vows to spend the rest of his life restoring function to kids who are born with congenital facial abnormalities.

Dr. Gibreel says, “Kids deserve to look normal, and sometimes they are born with cleft lips or cleft palates. There is nothing harder in life than to be a child whose face does not function normally or look normal. I decided to spend the rest of my life helping these kids.”

Karim Bakri, M.B.B.S., another mentor of Dr. Gibreel’s, says, “Dr. Gibreel personifies humanitarianism, as evidenced in all aspects of his life. I have worked with him in the operating room, and his technical skills are outstanding. He is detail oriented yet thoughtful.”

As chief resident, Dr. Gibreel has published 18 research articles, with six pending publications. He has also given back to the institution that he says gave him so much by educating junior residents and assisting with residency program development.

“I came to this country without my family, but the people at Mayo Clinic embraced me. Mayo changed me,” Dr. Gibreel says. “I met a team that believed in me and was willing to give me a chance. I’m a better person because of the mentors and role models who had such a positive influence on me.”

Dr. Gibreel graduated in May 2019 and is now continuing his education with a one-year fellowship in craniofacial surgery in California. He was awarded the prestigious Mayo Foundation Scholarship, guaranteeing him a position at Mayo Clinic when he finishes his fellowship.

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This story was originally published in Mayo Clinic Magazine.

Wed, Mar 4 6:00am · Providers investigate less invasive procedures for lung cancer and COPD

close in picture of bronchoscope threaded into a clear model of lung airway tubes

By Sara Nick

At Mayo Clinic, research and care often weave together. Many times this results in Mayo patients being the first to benefit from novel options for diagnosis or treatment. For instance, pulmonologists are testing the potential for new, minimally invasive procedures to diagnose and treat conditions including lung cancer and chronic obstructive pulmonary disease (COPD).

“The spectrum of this work spans from new device development to clinical practice, all aimed at providing better options for patients,” says Sebastian Fernandez-Bussy, M.D., interventional pulmonologist Mayo Clinic in Florida. “Research on these procedures furthers Mayo’s commitment to advancing patient care infused with new knowledge and innovative treatments.”

Toward a one-stop shop for lung cancer

Dr. Fernandez-Bussy and colleagues led by Janani Reisenauer, M.D., thoracic surgeon and interventional pulmonologist at Mayo Clinic in Minnesota, are assessing the ability of a new technology to diagnose lung cancer.

“Lung cancer starts with a
lung nodule, which we can see on a CT scan. But the scan can’t tell us whether
the nodule is malignant,” says Dr. Fernandez-Bussy. “We need a biopsy
for diagnosis, but some of the current biopsy techniques are invasive and pose
a risk of complications.”

Instead, the investigators are finding that a procedure known as robotic bronchoscopy could be used in a minimally invasive fashion to test lung nodules. In this outpatient procedure, a flexible tube attached to a lens and focusing ring, called a bronchoscope, is placed through the mouth of a patient. The tube is guided by a mechanical arm connected to a console and screen. The console provides doctors with precise control over the bronchoscope, allowing them the ability to navigate through tiny airways – less than 5 millimeters in size – to reach a lesion deep in the lung. They believe this technique will result in increased precision and reduced complications compared to current bronchoscopic biopsy methods.

In addition to tumor diagnosis, the
experts’ eventual hope is that robotic bronchoscopy could be used to treat lung
cancer. Bronchoscopic tubes are hollow, allowing specialists to insert a
catheter that could be used to deliver various treatments to the lesion.

“Ideally, we envision a
one-stop shop someday, where a patient’s lung tumor could be diagnosed, staged,
and treated in a single, incisionless outpatient procedure,” says Dr.
Fernandez-Bussy.

Clearing up COPD’s cough

According to the Centers for Disease Control and Prevention, approximately 16 million people in the U.S. are living with COPD. This inflammatory lung condition causes obstructed airflow from the lungs, and it’s one of the leading causes of disability in the country. Among COPD’s conditions is chronic bronchitis, a productive cough that occurs in bouts of three months or more over multiple years.

Dr. Fernandez-Bussy is involved
with a multi-center collaboration exploring the use of bronchoscopy to treat
chronic bronchitis symptoms and improve quality of life for COPD patients who
aren’t responding to other treatment options such as medication or inhalers. The
procedure involves threading a catheter through a bronchoscope to deliver an
electrical field aimed at decreasing the number of goblet cells in the airway,
which are responsible for producing mucous and inflammation.

Dr. Fernandez-Bussy also led a team that recently introduced a treatment to improve symptoms and quality of life for emphysema patients at Mayo Clinic in Florida. In emphysema, the air sacs in the lungs are damaged and over time rupture leaving a large air filled cavity. The new treatment, called endoscopic lung volume reduction, uses a bronchoscope to place one-way valves that deflate the ineffective part of the lung, making space for the “healthier” part of the lung to work. In 2019, Mayo was the first medical center in Florida to perform this minimally invasive treatment. Mayo Clinic in Florida and Rochester are two of only a few medical centers nationwide offering the procedure.

“Mayo’s close ties between
research and technology, and the teamwork between specialists here, make it
possible for us to bring state-of-the-art lung treatments to patients,”
says Dr. Fernandez-Bussy.

Watch this video to learn more about robotic bronchoscopy.

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Mon, Feb 17 6:00am · AI system helps individualize treatment people diagnosed with depression

Dr. Athreya sitting on a ledge in front of a window with scientific writing on it, and Rochester, Minnesota, skyline visible through the window.

When searching for an exact diagnosis through a myriad of complex and serious factors spread across millions of data points, it helps to have a powerful magnifying glass — and another expert point of view.

Enter Arjun Athreya, Ph.D., an engineer by trade who has a knack for bringing together data science algorithms and computing technology to predict events relating to potential disasters lurking within mission-critical cybersecurity infrastructure.

Dr. Athreya is the inaugural doctoral graduate of the Mayo Clinic and University of Illinois Alliance for Technology-Based Healthcare Fellowship program. Now, as a new Mayo Clinic faculty and staff member within Molecular Pharmacology and Experimental Therapeutics, the electrical and computer engineer has his sights set on health care.

Dr. Athreya developed a system for Mayo Clinic that uses artificial intelligence approaches ranging from machine learning to probabilistic graphs to better indicate treatment prognoses in people diagnosed with depression — the leading cause of medical disability worldwide. The system works by identifying patterns within patient history and other relevant data to predict which treatment option is best for the patient’s condition.

“In working with physicians, I learned that finding a diagnosis or treatment prognosis for a complex condition using the huge volumes of data generated from each patient can be like searching for a needle in the haystack,” Dr. Athreya says. “I try to create a magnifying glass to narrow the possibilities down and support the physician’s medical expertise.”

How do AI and machine learning fit into health care?

Mathematical formulations of AI methodologies can discover patterns in a patient’s data — such as genome, microbiome and imaging data — that can explain unique characteristics of the specific patient, allowing for the right treatment to be chosen at the right time and right dose to achieve the therapeutic benefit.

“When people hear AI, they usually feel like they’re going to be replaced by machines,” he says. “First, no doctor will be replaced, as I argued in my doctoral dissertation. Instead, I want to show that AI-based tools serve as an interactive companion to the physician, a technological innovation that assists clinicians in their patient care delivery.”

environmental picture of Dr. Bobo

William Bobo, M.D., is one of the physicians who collaborates with Dr. Athreya as part of a research team that is looking to personalize the treatment of major depression. A variety of treatment methods exist, but because of the timeline required to monitor effects — sometimes spanning several years — patients often grow weary of the process.

“Precision is of utmost importance in medicine,” Dr. Bobo says. “We work to give patients a more accurate diagnosis earlier, to spare them the suffering of their symptoms and the frustration they have.”

By combining the two mutually exclusive fields of direct patient care and data analysis, the team is able to answer that need. Dr. Bobo thinks this unique spirit of collaboration at Mayo Clinic is what makes the approach successful.

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This story originally appeared in Mayo Clinic Magazine.

Read a related article.

Fri, Feb 14 9:44am · Filling hearts instead of test tubes

Merrick Ducharme sitting on the carpeted floor in a playroom with a young boy, playing with action figures.

Editor’s note: This story is not about Mayo Clinic research, but rather about a part of a researcher’s life that builds hope in little hearts, and gives him joy.

It’s 10 a.m. on a Thursday, and Merrick Ducharme is up to his elbows (OK, his wrists) in slime. The gooey, gluey mixture is not one Ducharme, a research assistant at Mayo Clinic, concocts in the pulmonary lab where he spends most of his day. Instead, he’s mixing up the medicine at Mayo Clinic Children’s Center, where he volunteers each Thursday morning. “I try to make the kids forget they’re in the hospital,” Ducharme tells us. “I try to make them smile.”

Ducharme prepared for his research position at Carleton College, where he majored in biology. But he prepared for his volunteer position at home, where giving back was part of the Ducharme family game plan. “Our parents taught us about giving,” he says. “They talked a lot about sharing your gifts.” The family even started a charity together — Thanksgiving in a Bag — after noticing that a food shelf where they volunteered was low on supplies around the holiday. After creating a flyer listing items needed for a Thanksgiving meal, they distributed the fliers and encouraged people to fill a bag with the items and donate them to a food shelf. “We handed them out at church, school and to our sports teams,” Ducharme says. More than 10 years after launching, Thanksgiving in a Bag is still going strong. “There have been thousands of pounds of food collected and distributed,” Ducharme says.

After Ducharme told a colleague about Thanksgiving in a Bag, she told him about her experiences as a volunteer in Mayo’s pediatric center. Then she encouraged him to volunteer there, too. It was an easy sell. Not only does Ducharme have a big heart, he tells us he’s a big kid at heart. “I’ve always loved little kids,” he says. “Playing with kids is an easy way to volunteer.”

Two women and Merrick Ducharme, all in columbia blue volunteer jackets, poised to distribute acrylic paints from a cart full of craft materials.
Merrick Ducharme and some fellow volunteers get ready for some messy fun.

While Ducharme isn’t afraid to get his hands dirty (see: slime), he’s aware that his volunteer role is about more than fun and games. It’s about letting kids — and their parents — know they’re not alone, a way to demonstrate care and give hope. “Hope is my favorite thing about medicine, and there are all kinds of ways of giving hope at Mayo,” Ducharme says. “Surgeons give hope through what they do. Volunteers give hope by being positive and optimistic, and helping patients forget why they’re here.”

Ducharme tells us meeting patients and their families has altered his perspective on life. “I’ve met people who are going through otherworldly circumstances,” he says. “I met a teenager who’s had 60 operations. That would be a lot of operations even for someone at the end of a long life, and he’s just a kid. But he was still able to joke and laugh and be positive.” Ducharme says it was “a reminder of how many things we take for granted.”

Volunteering has also altered Ducharme’s thoughts on the future. He left college imagining a career in neurology or psychiatry. Now, he’s leaning toward pediatrics. “The kids have affected me more than I expected,” he tells us. “My heart just feels full when I leave there. I look forward to it every week. I feel like I’m doing what I’m supposed to be doing.”

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This story was originally published on In the Loop, a subscription-based newsletter and blog that gives a unique perspective on happenings at Mayo Clinic.

Tue, Feb 11 6:00am · Clinical Decision Support: Making It Easy to Do the Right Thing

According to the Office of the National Coordinator for Health Information Technology, clinical decision support provides clinicians, staff, patients or other individuals with knowledge and person-specific information, intelligently filtered or presented at appropriate times, to enhance health and health care.

Matthew Warner, M.D.

At Mayo Clinic there are a range of activities surrounding the development, optimization and implementation of clinical decision support tools.

In a new podcast from the Bow Tie Bandit and Mayo Clinic Laboratories, hear from Matthew Warner, M.D., a Mayo Clinic anesthesiologist. In the podcast you will learn what clinical decision support is, as well as some of the successes and pitfalls of implementation.

Dr. Warner will also talk about some of his experiences with clinical decision support, specifically with regards to patient blood management.


Justin Kreuter, M.D.

Clinical Decision Support: Making It Easy to Do the Right Thing is part of a series of podcasts hosted by Justin Kreuter, M.D., (aka the Bowtie Bandit), discussing various topics related to lab medicine.

Mayo Clinic Laboratories is a global reference laboratory that helps health care providers worldwide advance patient care, strengthen their practices, and broaden access to specialized testing.

Through partnerships with clinicians at Mayo Clinic and health care providers around the world, Mayo Clinic Laboratories is able to offer the most sophisticated test catalog in the world. It is because of these daily collaborations that the Labs’ subspecialized laboratories continue to be a critical component to patient care at Mayo Clinic.

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Fri, Feb 7 6:00am · Toxic Protein, Linked to Alzheimer's and Other Neurodegenerative Diseases, Exposed in New Detail

By Zuckerman Institute Communications Staff

Alzheimer’s disease brain pathology is illustrated using thioflavin-S fluorescent microscopy, which reveals both neurofibrillary tangles (flame-shaped structures) and amyloid plaque pathology (rounded structures). Through the use of the amyloid brain scanning, we are able to visualize amyloid accumulation in the brains of living individuals – visualized with warmer colors. Read about a related discovery at Mayo Clinic.

The protein tau has long been implicated in Alzheimer’s and a host of other debilitating brain diseases. But scientists have struggled to understand exactly how tau converts from its normal, functional form into a misfolded, harmful one. Now, researchers at Columbia University’s Zuckerman Institute and Mayo Clinic in Florida have used cutting-edge technologies to see tau in unprecedented detail. By analyzing brain tissue from patients, this research team has revealed that modifications to the tau protein may influence the different ways it can misfold in a person’s brain cells. These differences are closely linked to the type of neurodegenerative disease that will develop — and how quickly that disease will spread throughout the brain.

The study, published today in Cell, employed two complementary techniques to map the structure of tau and decipher the effects of additional molecules, called post-translational modifications (PTMs), on its surface. These new structural insights could accelerate the fight against neurodegenerative diseases, by helping researchers identify new biomarkers that detect these disorders before symptoms arise and design new drugs that target specific PTMs, preventing the onset of disease before it wreaks havoc on the brain.

“Tau has long been a protein of significant interest due to its prevalence in disease,” said Anthony Fitzpatrick, PhD, a Principal Investigator at Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute who led the study. “In today’s publication, we lay out compelling evidence that PTMs play an important structural role in tauopathies, the collection of neurodegenerative diseases characterized by toxic buildup of misfolded tau.”

Collectively, these results suggest that PTMs may not only be serving as markers on the proteins’ surface, but are actually influencing the behavior of tau.

No two tauopathies are exactly alike, continued Dr. Fitzpatrick, who is also a member of Columbia’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. Each affects different parts of the brain — even different cell types — which can lead to different symptoms. Alzheimer’s, for example, arises in the hippocampus, and so affects memory. Chronic traumatic encephalopathy, a disorder most often seen in survivors of traumatic brain injury, can lead to problems with movement, memory or emotion, depending on which areas of the brain are affected.

Abnormal tau protein (brown) in a sample of the brain in Alzheimer’s disease. Tau is deposited throughout the gray matter but not in the underlying white matter. The Mayo Clinic brain bank was the source of the tissues used in this research.

Scientists have used traditional imaging techniques to find clues to how tangles of tau, comprised of individual fibers, or filaments, are implicated in these diseases. But painting a complete picture has proven difficult.

“The brains of patients with neurodegenerative diseases are easy to identify: entire sections have been eaten away, replaced by large clumps and tangles of misfolded proteins like tau,” said Tamta Arakhamia, an undergraduate at Columbia’s School of General Studies, a research assistant in the Fitzpatrick lab and the paper’s co-first author. “However, tau filaments are 10,000 times thinner than the width of a human hair, making them extraordinarily difficult to study in detail.”

To address this challenge, Dr. Fitzpatrick recently pioneered the use of cryo-electron microscopy, or cryo-EM, to visualize individual tau filaments from diseased human brain tissue. Cryo-EM is a Nobel Prize-winning technology developed, in part, by researchers at Columbia University. Cryo-EM images samples using a beam of electrons and has proven indispensable for investigations into extremely small biological structures. Using cryo-EM, Dr. Fitzpatrick’s team has reconstructed the structures of tau filaments, providing new insights into how they form, grow, and spread throughout the brain.

For all its ability to provide highly detailed snapshots of proteins, cryo-EM has limits. To overcome these limits, Dr. Fitzpatrick and his team to paired it with a second technology: mass spectrometry.

“Cryo-EM does not provide a complete picture because it cannot fully recognize the microscopic PTMs on tau’s surface,” said Christina Lee, an undergraduate student at Columbia College, a research assistant in the Fitzpatrick lab and the paper’s co-first author. “But mass spectrometry can pinpoint the chemical composition of PTMs on the surface of tau.”

Working with co-corresponding author Leonard Petrucelli, PhD, Ralph B. and Ruth K. Abrams Professor of Neuroscience at Mayo Clinic in Florida, and Nicholas Seyfried, PhD, professor of biochemistry at Emory University School of Medicine, the researchers used cryo-EM and mass spectrometry to analyze the brain tissue from patients diagnosed with two tauopathies: Alzheimer’s disease and corticobasal degeneration, or CBD. CBD is a rare but extremely aggressive tauopathy, affecting only one in every 10,000 people. Unlike Alzheimer’s, which is thought to arise due to a number of factors including tau, CBD is primarily associated with misbehaving tau proteins.

“Studying a primary tauopathy like CBD helps us to figure out how tau becomes toxic to brain cells,” said Dr. Petrucelli. “We hope to extrapolate that knowledge to secondary tauopathies, such as Alzheimer’s disease.”

The scientists’ analysis of brain tissue samples revealed several key insights. Most notably, the researchers found that cross-talk between PTMs on the surface of tau influences the structure of the tau filaments, contributing to differences in tau filaments observed across the various tauopathies — and even variations from patient to patient.

“Collectively, these results suggest that PTMs may not only be serving as markers on the proteins’ surface, but are actually influencing the behavior of tau,” said Dr. Fitzpatrick, who is also an assistant professor of biochemistry and molecular biophysics at Columbia’s Vagelos College of Physicians and Surgeons.

Moving forward, Dr. Fitzpatrick and his team plan to expand this work to other tauopathies. Today’s findings on Alzheimer’s and CBD hold immense promise for the field, particularly in the development of new disease models — such as lab-grown organoids, or mini-brains — that may serve to accurately recapitulate what is actually happening in the brains of patients.

“Our findings will inspire new approaches for developing diagnostic tools and designing drugs, such as targeting PTM vulnerabilities to slow disease progression,” said Dr. Fitzpatrick. “Neurodegenerative diseases are among the most complex and distressing class of illnesses, but through our work and that of our colleagues and collaborators, we are building a roadmap toward successful diagnostics and therapeutics.”

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