For the millions of people who could face a cancer diagnosis this year, it's vital to have all therapeutic options available.

But in some cases, the drugs used to treat cancer can cause other health problems during treatment or later. One example is a class of drugs called anthracyclines, which are derived from bacteria found in Italian soil decades ago. This group of about six chemotherapy drugs has been used since the 1960s to treat leukemia, lymphoma, sarcoma and breast cancer, as well as other cancers that have spread from their original site. But a serious side effect of anthracyclines is heart damage either during treatment — which means patients must stop using it — or weeks, months or even years later. This heart damage can decrease the quality and duration of a former cancer patient's life.

To find the best path for care, a team of clinician-researchers and discovery scientists report on a potential way to prevent or heal heart damage when anthracyclines are used to treat cancer. The paper is published in Circulation Research.

Treatment to Toxin

Xiaolei Xu, Ph.D., who directs the Zebrafish Genetics Laboratory at Mayo Clinic and specializes in studying cardiac disease, combined forces with Joerg Herrmann, M.D., director of the Cardio-Oncology Clinic at Mayo Clinic.

"The liaison between basic and clinical science is critical for advancing the medical field in general and especially this field," says Dr. Herrmann. "Only through new research discoveries at the bench and their translation to the bedside are we able to improve care and outcomes of patients who are in dire need of it."

Together the researchers are working to uncover the basic mechanisms of anthracycline heart failure in preclinical models and then translate that knowledge into drug treatments for patients.

"We leveraged zebrafish as a more efficient vertebrate model for the initial step of the drug screen," says Dr. Xu. "A higher number of drugs can be assessed in the zebrafish model, and the top-ranking drugs are also effective in treating anthracycline-induced cardiotoxicity in a mouse model of the disease."

Using an embryonic and then an adult zebrafish model of anthracycline-induced cardiotoxicity with the drug doxorubicin, the researchers identified a key cellular process linked to heart damage. Called "autophagy," this process recycles and disposes of waste proteins and damaged cellular machinery, such as mitochondria. In zebrafish, researchers could see that soon after treatment with doxorubicin, heart cells increased the process of autophagy. But over time, autophagy decreased, and the heart became dysfunctional. When researchers increased the availability of a protein crucial to autophagy, that process rebounded, and the zebrafish heart function improved.

The scientists also tested medications linked to increasing autophagy and then tried those drugs in a mouse model of anthracycline-induced cardiotoxicity. In all models, the drugs used to boost autophagy increased damage in the early phase of treatment with doxorubicin. But the drugs restored the process of autophagy and thereby not only prevented further cellular damage, but also recovered heart function in the late phase.

"This discovery addresses conflicting results that have been lingering in the anthracycline-induced cardiotoxicity field for many years and could benefit many cancer patients directly," says Dr. Xu.

From a clinical perspective, Dr. Herrmann says the approach to anthracycline cardiomyopathy has focused largely on prevention, and efforts to improve treatment of the condition are limited.

"Full improvement in cardiac function with standard therapies is seen in only 10% of patients with anthracycline cardiomyopathy, and if occurring, it takes often years," Dr. Herrmann says. "Our ongoing studies therefore address a very important clinical need."

With funding from Mayo's Center for Biomedical Discovery and the Department of Cardiovascular Disease focusing on bringing together discovery and clinical scientists, the team hopes to translate Dr. Xu's zebrafish findings. They are working to further mechanistic insight and develop clinical trials to define the best treatment for patients who develop a decline in heart function as a consequence of therapy with anthracyclines such as doxorubicin.

In addition to Drs. Xu and Herrmann, other authors are Yong Wang, Ph.D.; Xiaoguang Lu, Ph.D.; Xiaoping Wang, Ph.D.; Qi Qiu, Ph.D.; Ping Zhu, Ph.D; Lin Ma; Xiao Ma, Ph.D; Xueying Lin, Ph.D.; and Wei Wang Ph.D. For funding information and author disclosures, see the paper.

— Sara Tiner, Jan. 31, 2022

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"One of the questions I got was how does gravity work, and I was like, 'Oh that's a great question," says Hirotaka Ata, M.D., Ph.D., one of the volunteer scientists. "I talked about how everything has a little bit of a pull, but the bigger it is, the stronger the pull. I don't know what they took away from it because they're second graders, but I figured they know about the planets and things like that."

The second graders in question were taking part in a lesson on the zebrafish life cycle. And, no, in second grade, it's not a huge leap from fish to gravity. The lesson is part of the Integrated Science Education Outreach program started as a collaboration between Mayo Clinic, Winona State University ― Rochester and Rochester Public Schools. It brings experiential science lessons and scientists to the classroom with the goal of making science fun and interactive so in the future, there are more scientists and more scientists from diverse backgrounds.

"We need more scientists from underrepresented populations because the complexity of the problems hitting us as a community require more minds, ideas and perspectives," says Chris Pierret, Ph.D., a scientist at Mayo who coordinates the program. "Trying to find new voices in science isn't just the right thing to do. It's the only possible solution."

Get Ready for Anything

On this day in early 2021, the volunteers are all from Mayo Clinic. They are one of the few approved visitors to the school during the pandemic and are taking all the required precautions. Dr. Ata is a student in Mayo Clinic's M.D.-Ph.D. Program (he has since left Mayo for a residency on the East Coast). The others study nephrology, orthopedic surgery or radiology. Two are here to help out in the Spanish-speaking immersion classroom. Michael Ekker, the in-school organizer, helps orient new volunteers to where the students are in the lesson, telling them more about the zebrafish embryos.

"They've grown up enough today so that they look like fish," Ekker says, pointing out the eye and the tail. Through the weeklong program, the students look at the fish every day, drawing and discussing how the eggs mature. But one of the most important long-term aspects of the program is that the kids get to interact with a scientist.

"Get ready for anything and everything," Dr. Ata says as the volunteers wait to go into the classroom. "Another question I got was, "Do you guys ever go back in time," he says, clearly worrying the other volunteer. But it was fine, he said, and he told the kids that while they can't go back in time physically, scientists can use the layers of the ground to find out about the past.

"And then they dove into dinosaur bones and all that kind of thing," Dr. Ata says.

Teachers Teaching, Scientists Bringing the Lab

The program, often abbreviated to InSciEd Out, began in 2008 and received funding in 2009 from Mayo Clinic's Center for Clinical and Translational Science (often shortened to CCaTS and pronounced as "see-cats"). The center is a hub for advancing research, especially efforts that are developed in collaboration with communities that could benefit from the research results.  

"InSciEd Out began as a partnership with schools and educators, trying to open up the pathway of science to more students," says Dr. Pierret. "As we did so, we realized we were interacting with the community in a way that brought folks forward and in a way that CCaTS has been trying to do through community engagement and through special populations. So it became a very natural partnership for CCaTS."

They started in the Rochester, Minnesota, school district. After gathering a few years of data, scientists from Mayo published a peer-reviewed article in the journal Zebrafish. They defined the program goal as improving science proficiency in the local school system through the power of partnership, writing, "Put simply, teachers are not asked to run a laboratory, and scientists are not asked to manage a kindergarten classroom." Instead, they write, scientists and teachers contribute their individual expertise to improve science education.

Critical Thinking and Observation: Skills for Life

In one of the four classrooms, the kids are grouped around the laptop.

"Is that the tail?"

"It is moving!"

"The tail looks like a banana."

As the students observe the zebrafish lifecycle, they draw what they see on the computer screen. After everyone has had a chance to draw, the scientist leads them through the process of comparing the pictures. She asks, "Does the image look different today than yesterday?" And "Why do you think it changed?" The discussion ranges from how a single cell becomes something like a spine or an eye, to the role of the brain in the body. Then a student asks if the fish will be grown up by tomorrow. The teacher reminds the student of the life cycle, and then the scientist asks, "How long do you think zebrafish live?"

Silence.

"How about dogs?" she tries. Someone shouts, "30."

"Ok, so how old are the oldest people you know?" she says.

"One-hundred," says one student. "One-hundred and ten," says another one.

The teacher breaks in, "We're not going to be silly," and the next chorus includes numbers in the 60- and 70-year-old range.

"So if dogs don't live as long as humans," asks the scientist, "then do you think fish would?"

Thoughtful silence.

This experience of critical thinking, associating information to make reasonable deductions is a bonus in the zebrafish life cycle curriculum. 

Scientists of the Future

Despite the occasional foray into gravity, the students do learn the objectives set out by the teacher. An added benefit is that the kids are exposed to volunteers that show them that scientists can be anyone.

"All of the research we've seen shows that if students are able to see a role as something done by someone they look like it makes a huge difference in whether they think they could do it," says Ekker.

When asked to draw a picture of a scientist, he continues, most kids will draw someone who looks sort of like Einstein. But after the zebrafish lesson — where volunteers tend to represent the spectrum of ethnicities and gender — the drawings change.

"At the end, you get fewer old white-haired guys in a lab coat," he says. "We're not trying to teach that lesson to them, right? We want it to be kind of passively learned throughout the process."

In addition to Minnesota, InSciEd Out is now present in Florida, Illinois, Puerto Rico, Ghana and India.  They've adapted their programming framework to address infectious disease transmission and mental health, and to support teacher-led research in the classroom.

For more information on the program, visit the InSciEd Out website.

- Sara Tiner, September 2021

The post Science Saturday: Zebrafish, Mayo scientists inspire young students to learn science appeared first on Mayo Clinic News Network.

Rather than simply telling kids vaping is harmful to their health, one Rochester school took a different approach to prevention, letting students figure it out themselves through hands-on research.

Ever since vaping caught on among kids as a perceived safer alternative to smoking, medical officials have released statement after statement dispelling that belief. But sometimes, telling kids not to do something can sometimes have the opposite effect. That's why one middle school in Rochester took a different approach to vaping prevention. Rather than simply telling kids vaping is harmful to their health, they let them figure it out for themselves in a safe and fun environment.

Last fall, students at Lincoln K-8 District-Wide School began studying the effects of vaping solutions on developing zebrafish embryos, as the Rochester Post-Bulletin and KARE11 News report. The research was part of the school's participation in InSciEd Out, a partnership between the InSciEd Out Foundation, Rochester Public Schools and Mayo Clinic created to "engage students and empower teachers through research-based experiential learning."

Read the rest of the article on In the Loop.
________________________________________________

This story originally appeared on the In the Loop blog.

The post In the Loop: Zebrafish help students see dangers of vaping from the InSciEd Out appeared first on Mayo Clinic News Network.

For Alaa Koleilat, pursuing a doctorate is a tale of two mentors with a few tails thrown in for good measure. With the help of her advisers, and tanks full of zebrafish, she’s taking on hearing loss and finding solutions across the research continuum.

“I love it,” says Koleilat, a student in Mayo Clinic Graduate School of Biomedical Sciences. “I’m trying to develop the skills to work at the lab bench and do experiments and also look at the broader picture and the business side of biomedical science.”

Koleilat chose the clinical and translational science track in the graduate school. The courses are created in collaboration with Mayo Clinic’s Center for Clinical and Translational Science and aim to train students to streamline research “translation,” the process of bringing medical advances to clinical care. Mayo doctoral students in clinical and translational science typically have dual mentors and, now in her fourth year, Koleilat is supported by:

• Stephen Ekker, Ph.D., is a geneticist with an entrepreneurial streak. In his lab he focuses on identifying key genes in organ and blood vessel development. He is director of Mayo Clinic’s Zebrafish Facility and Mayo Clinic’s Office of Entrepreneurship, as well as dean of Mayo Clinic Graduate School of Biomedical Sciences.

• Lisa Schimmenti, M.D., is a physician-scientist. A clinical geneticist, Dr. Schimmenti heads a lab that focuses on congenital hearing loss. She also chairs Mayo’s Department of Clinical Genomics, whose research furthers understanding of genetic-based diseases and helps improve prevention, diagnosis and treatment by tailoring care to each patient’s genetics.

With their expertise and Koleilat's drive, the team is taking on hereditary hearing loss and access to hearing tests.

“Having two mentors has given me a broader insight into various facets of science,” Koleilat says. “Dr. Ekker brings a perspective of science that I never thought about before in terms of biotech, and Dr. Schimmenti has provided me with the aspect of clinical care and what my research means to patients.”  

Attuned to Hearing

Koleilat gained an appreciation for hearing at a young age. She developed abnormal speech at age 3 when fluid collected in her ears. Speech therapy erased the abnormality, but she never lost awareness of the effects of impaired hearing. For her master’s degree at the University of Minnesota, Koleilat focused on Usher syndrome, a genetic disorder that is the leading cause of the combination of deafness and blindness. Dr. Schimmenti, then on the university’s faculty, was her mentor. Dr. Ekker served on her thesis committee.

At Mayo Clinic Graduate School of Biomedical Sciences, Koleilat is continuing that research in a way that takes her from the lab to patient care.

“We are focused on making sure our science is translatable to the clinic,” Koleilat says. “We always have patients in mind, even at the lab bench, which gives students big-picture outlooks on their projects. Being reminded of the greater purpose of our work is truly inspiring.”

“We want to empower our future leaders to have professionalism on the medical side and the research side, to leverage and understand both sides,” Dr. Ekker says. Dr. Schimmenti agrees: “We’re helping Alaa find a treatment for the same problem from two different perspectives.”

In her first year of graduate school, Koleilat took the unusual step of choosing a rotation in a clinical department, Otorhinolaryngology (ear, nose and throat), to learn more about how hearing loss affects patients and how it is evaluated and treated. 

“Even though it was not basic science, I could see different aspects of hearing loss in patients, and that informed me about the bigger picture of my hearing research at the lab bench,” she says.

At the end of that year, Koleilat joined Dr. Ekker’s zebrafish genetics lab. For her thesis, she chose a pioneering challenge: Identify the first drugs that could restore hearing in Usher syndrome type 1, marked by profound hearing loss or deafness at birth, severe balance problems that delay sitting and walking, and progressive vision loss, usually starting before age 10.

Hearing and Language

The current treatment for hearing loss is hearing aids or a cochlear implant. There is no pharmaceutical treatment for hearing loss, but Koleilat hopes to change that: “No one has asked, ‘Why not take medication every day to preserve hearing?’ We’re trying to do something that no one else has ever done.”

Hearing provides the foundation for children to learn language and speech. A medication that restores hearing, giving youngsters more time to learn communications skills before Usher causes deafness, could produce lifelong improvement in quality of life, Dr. Schimmenti says.

Disrupting Genetic Signals

Researchers have linked Usher syndrome to mutations in at least nine genes. In the inner ear, these genes make proteins involved in the development and function of sensory hair cells, which help to transmit sound and signals to the brain. With Usher syndrome, gene mutations lead to degeneration or loss of these hair cells.

For example, the MYO7A gene makes a protein that plays a role in hair-like projections called stereocilia that line the inner ear. Stereocilia bend in response to sound waves, converting sound waves to nerve impulses that are transmitted to the brain. The bending of stereocilia also help maintain balance and orientation in space. With a mutation of the MYO7A gene, the most common cause of Usher syndrome, the protein doesn’t function properly, preventing hair cells from communicating with the auditory nerve.

Koleilat realized that calcium also plays a role in sending signals in hair cells.

“We believe there’s not enough calcium to get the job done,” she says, “so why not just try to restore the calcium?”

Koleilat chose to focus on medications that stimulate the calcium channel in the hair-cell membrane, which initiates and regulates many intracellular processes, including neurotransmission.

“We want to force it open to allow more calcium ions into the cell,” says Koleilat, who hypothesizes that increased calcium will release more neurotransmitters, increasing the chance that hair cells can send sound-related signals to the brain.

Fishing for Answers

Drs. Ekker and Schimmenti head two zebrafish labs at Mayo Clinic, and much of Koleilat’s research involves the striped Asian minnow. Because their genome is nearly 70 percent identical to humans and they grow quickly, zebrafish are the leading non-mammalian vertebrate model of human development and disease.

Zebrafish have anatomy similar to the human inner ear. Using zebrafish models for Usher syndrome type 1 that exhibit no startle response to sound and swim in a circle due to impaired balance, Koleilat’s team was the first to quantify physiological changes associated with Usher syndrome in zebrafish. Most notably hair cells have fewer neurotransmitter-containing structures on smaller contact sites with neurons.

The team also used zebrafish with the MYO7A mutation to screen potential medications. In testing the concept on zebrafish embryos in medicated water, drugs that boost the hair cell’s intake of calcium offset at least some of the defects that cause deafness.

To accelerate the development process, the team then identified FDA-approved medications with the same action, known as calcium-channel agonists. Although intended for other conditions, the medications have already undergone studies for safety and proper dosing.

“Now it takes 20 years and billions of dollars to develop and test a new pharmaceutical in patients,” Dr. Schimmenti says. “If we find the right off-the-shelf drug, we can resynthesize it to be more efficacious and to have no side effects on other parts of body.”

So far, the team has tested three medications. One produced a startle response to sound and physiological change at the cellular level - an increase in the number of neurotransmitter-containing structures and the size of the contact sites. The same medication also produced significant improvement in swimming behavior.

“It may not be the exact drug to treat hearing loss caused by variants in MYO7A, but it’s paving the way for a new pharmacotherapy,” Koleilat says.  

The Student Becomes a Colleague

As Koleilat nears completion of her Ph.D., Drs. Ekker and Schimmenti say their student has become a mature scientist.

“She can think independently, and she is driving the research,” says Dr. Schimmenti, who now thinks of Koleilat as her colleague.

“She’s a really impressive future leader,” says Dr. Ekker, who can envision Koleilat becoming a principal investigator or the CEO of a biotech company.

Koleilat, who plans to seek a postdoctoral fellowship in genetics or genomics, traveled to Germany to present her research at an international symposium on Usher syndrome, where she met and answered questions from patients hoping for the kind of treatment she is trying to develop.

“It was a really profound moment for me,” she says. “Knowing there’s someone out there waiting for this gives more meaning to your work and sparks the flame of motivation. It made me realize that Mayo is training me to be the expert in my field.”

- Jon Holten, July 2019

The post Science Saturday: A tale of two mentors and a tank full of zebrafish appeared first on Mayo Clinic News Network.

Lisa Schimmenti, M.D. has always been fascinated with Helen Keller and all she accomplished, in spite of being blind and deaf from a very young age. As the newly appointed chair of Mayo Clinic’s Department of Clinical Genomics and a medical geneticist, Dr. Schimmenti cares for patients with similar conditions.

In her clinical practice, she sees children and adults with Usher syndrome, a rare genetic condition that causes deafness or profound hearing loss at birth and blindness by the time a child turns five. With support from the Center for Individualized Medicine and the Department of Otorhinolaryngology, Dr. Schimmenti is using zebrafish to search for drug therapies that could help restore hearing for these patients.

During her career, she’s seen how genomic discoveries have uncovered the causes of many rare diseases and led to the development of new targeted treatments for many more common diseases like cancer and heart disease. Now in her new role overseeing the Department of Clinical Genomics, Dr. Schimmenti is working to extend genomics medicine across all specialties at Mayo Clinic.

“Our clinical geneticists and genetic counselors are collaborating with all departments to facilitate the use of the latest genomic testing technologies to help improve care for all patients.” – Lisa Schimmenti, M.D.

“Our clinical geneticists and genetic counselors are collaborating with all departments to facilitate the use of the latest genomic testing technologies to help improve care for all patients,” says Dr. Schimmenti.

Here’s a closer look at how she’s using the latest genomics tools in her own research to uncover a treatment for hearing loss.

Restoring hearing to boost language development

For newborns diagnosed with Usher syndrome, the only current treatments available for hearing loss are devices such as hearing aids or cochlear implants. However, cochlear implants cannot be implanted until an infant is 12 months old and many infants do not benefit from a hearing aid alone.

“If we can identify a drug to improve hearing, we can help newborns hear sooner, at a time when language development is so critical. They may then be able to use a hearing aid while awaiting a cochlear implant,” says Dr. Schimmenti.

Zebrafish – the perfect model for drug discovery

Dr. Schimmenti and her team are using zebrafish, a type of freshwater fish, to test drug compounds to improve hearing.

“We are able to use zebrafish to model the conditions that we see in the clinic because they share 70 percent of their genes with humans. The same gene that causes Usher syndrome in humans also causes the syndrome in zebrafish,” says Dr. Schimmenti.

The research team tests different therapies by putting the medication into the water. They then measure changes in the hair cells on the zebrafish, which are an important link in the sensory process for hearing, to identify any changes.

The team’s early research results are promising. The next step is to test therapies that have been shown to improve hearing in mouse models.

“While we are early in the research process, the prospect of finding a drug to bypass some of the genetic defects in the sensory process that are causing deafness is very exciting. It’s possible that these therapies could also be applied to treat hearing loss caused by other conditions. For example, some cancer treatments can cause nerve damage and hearing loss. The implications of these discoveries could eventually be far reaching." – Dr. Schimmenti

“While we are early in the research process, the prospect of finding a drug to bypass some of the genetic defects in the sensory process that are causing deafness is very exciting. It’s possible that these therapies could also be applied to treat hearing loss caused by other conditions. For example, some cancer treatments can cause nerve damage and hearing loss. The implications of these discoveries could eventually be far reaching,” says Dr. Schimmenti.

A passion for genetics

Dr. Schimmenti became interested in genetics early in her medical training. However, she chose a different path before returning to genetics as the focus of her career.

“During my pediatrics training at Harbor-UCLA Medical Center, I saw many young patients with severe hearing loss and was surrounded by outstanding mentors who were working to uncover the genetic causes of these conditions. But at the time, the Human Genome Project, the first mapping of an entire human genome, had not been completed. Genomic discovery was in the early stages, so I chose to pursue a fellowship in critical care at Yale University rather than continue in genetics,” says Dr. Schimmenti.

As progress in genomic discovery continued and genetic variants linked to hearing loss were identified. Dr. Schimmenti decided to return to her true passion – working in the lab to uncover new therapies for the patients with rare genetic diseases that she cared for in the clinic.

She returned to University of Minnesota to complete her genetics fellowship and begin her work using zebrafish to better understand the genetic and molecular processes driving hearing loss.

And she’s never looked back.

“It’s exciting to use genomics to search for a drug that could treat hearing loss and make a real difference for patients. At the same time, I am excited to collaborate with all medical specialties across Mayo Clinic to see how we can extend genomics services to all patients and enhance individualized care for many conditions,” says Dr. Schimmenti.

Learn more about individualized medicine

For more information on the Mayo Clinic Center for Individualized Medicine, visit our blog, Facebook, LinkedIn or Twitter at @MayoClinicCIM.

See highlights from Individualizing Medicine: Advancing Care Through Genomics, which was held Sept. 12-13 in Rochester, Minnesota:

• CIM CON day 1 – Precision cancer care: ‘So much power’
• CIM Con day two: Unlocking the mystery of rare diseases
• CIMCON18 — how genomics discovery is transforming individualized care and the path forward

The post Meet Lisa Schimmenti: Searching for drug therapies to treat hearing loss appeared first on Mayo Clinic News Network.

Aquariums are arranged in neat, illuminated rows. Fins, tails and flashing stripes are visible in every direction. On the Mayo Clinic campus in Rochester, Minnesota, zebrafish act as research stand-ins for us. They are tiny heralds of solutions for patients with some of medicine’s most intractable problems.

But how can an aquarium fish help solve human disease? Because all living things are related.

Most of the genetic variants associated with human diseases can be found in zebrafish. Basically the differences between species arise from variations in the ways the parts of DNA are arranged. DNA is made up of nucleotides (As, Ts, Gs, and Cs) that together form into coherent instructions called genes that determine whether a creature has legs or fins.

Researchers have long used mammals like mice to study human disease. But zebrafish have become the model of choice in many medical laboratories in part because they breed more prolifically, hold more animals per research footprint and can be very resource friendly compared to other vertebrates.

An unlikely suspect
Biochemist Stephen Ekker, Ph.D., is the director of the Mayo Clinic Zebrafish Facility, aka the "Fish Farm."

As he gestures toward the aquariums bubbling all around, he explains, “With the combination of vertebrate biology like us, new gene editing tools such as CRISPR, new real-time imagers, and the ability to scale so we can test many scientific questions in parallel, the potential for zebrafish to impact and study health and disease seems limitless.”

Housing more than 65,000 adult fish and generating 10,000 larvae a day, the farm is used by dozens of Mayo researchers to study processes that are difficult or impossible to follow in other animals. From the moment the eggs in the tanks are fertilized, it’s possible to keep a close eye on developing embryos.

Because those embryos are transparent, they provide a window into development. Researchers can watch as organs form and hearts take their first beats. Also, whereas tumors develop over months or years in people, it only takes days or weeks for them to progress in the tiny fish. So with cancer tracing technology, it’s possible to watch the development of tumors in real time.

And that can help real patients. Sometimes, the cause of a tumor is a typo in one or more genes. To understand that error better, the same mutation can be edited into zebrafish, and the fish can be examined for similar symptoms. That, perhaps, is the most valuable thing about zebrafish as a model: They can be genetically manipulated.

Rewriting DNA
Biochemical researcher Shizhen Zhu, M.D., Ph.D., and her team engineered multiple lines of zebrafish to make it faster and easier to study neuroblastoma — the deadliest childhood cancer in the United States.

High-risk neuroblastoma often starts before birth, with symptoms appearing in infancy. It is rarely found in children older than 10. This cancer occurs when gene defects force fetal nerve cells (neuroblasts) to divide uncontrollably, forming tumors instead of becoming functional nerve cells. Some neuroblastomas grow and spread quickly, but others grow slowly and sometimes in very young children, the tumors even go away on their own.

Genomic analyses have identified an assortment of genes related to neuroblastoma susceptibility, including one called MYCN. Several years ago, Dr. Zhu and her colleagues engineered zebrafish that make high levels of MYCN. About 25 percent of the offspring from this line develop tumors. Next were zebrafish that overexpressed not only MYCN, but also a gene called ALK. About 70 percent of the offspring from this line developed tumors that grew to closely resemble human neuroblastomas.

Most recently, her zebrafish lines have clarified the relationship between MYCN and a gene called LMO1, which fuels the aggressive spread of neuroblastomas. A new line expressing the metastasis-causing form of LMO1 was crossed with a line overexpressing MYCN, resulting in eighty percent of the offspring developing neuroblastomas that metastasized. This is a promising result according to Dr. Zhu, because metastases, rather than primary tumors, are responsible for most deaths.

Dr. Zhu’s goal is to translate her findings into effective therapies for children.

Her engineered lines “provide a valuable platform for evaluating the effect of drugs on neuroblastoma,” creating targeted therapies to kill existing cancer cells and to still the metabolic pathways stirred up by susceptibility genes — so the cancer doesn’t come back.

Mitochondria: In sickness, in health
When researchers talk about genome editing, they’re often referring to rewriting the DNA in cell nuclei. But the cell’s mitochondria—where energy for the cell is generated—contain their own tiny genomes. And errors in mitochondrial genes negatively affect almost 1 out of every 2,500 people born in the U.S. each year.

Starting from scratch, one of Dr. Ekker’s research teams is using zebrafish small fry to develop tools to edit the mitochondrial genome. Moreover, as part of Dr. Ekker’s wider interest in modeling rare diseases, he has a different team looking directly at how mitochondria affect disease. They are, for example, using zebrafish to model the French Canadian form of Leigh syndrome — a rare, fatal, inherited disorder that affects the central nervous system, beginning in early childhood.

Zebrafish larvae engineered to have the inborn error for Leigh syndrome have much the same symptoms as human children. Their kidneys and hearts are close to normal. Their connective tissue and muscles are only somewhat affected. And their livers and brains are profoundly affected. When Dr. Ekker corrects the DNA error in the livers of the sick larvae, their liver function improves, but so does their neurological function. This may have positive implications for regenerative medicine, where a patient’s own cells can be harvested, tweaked and used as therapies.

From mitochondria to the ear
In addition to mitochondrial disease and cancer, zebrafish can also help with hearing loss. More than 70 percent of human genes have orthologs (genes in different species that evolved from a common ancestral gene) in zebrafish. Genetic variants that make people deaf make zebrafish deaf, too.

Lisa Schimmenti, M.D., Professor of Pediatrics at the Mayo Clinic and a longtime collaborator with Dr. Ekker, cares for children who have rare diseases associated with hearing loss.

She uses zebrafish to model the conditions she encounters in the clinic. “I feel like a kid in a candy shop with all the cool genomics tools I have access to,” Dr. Schimmenti says.

With some types of hearing loss, parts of the inner ear and brain that process sensory information are involved. In response, fish exhibit behaviors that parallel those of people. Currently, the only treatment options for patients with hearing loss are devices like hearing aids and cochlear implants. But Dr. Schimmenti believes that drugs could be found to bypass at least some of the genetic defects that cause deafness. Her team is screening candidate compounds by putting them directly in the water and monitoring the fish for changes in their responses to sound. Voila. The utility of zebrafish.

Drug evaluation may also help with hearing loss that isn’t genetic. Cancer treatments save lives but their side-effects may damage the nerves or structures associated with hearing. To prevent or detect hearing loss early when it can perhaps be reversed, Drs. Schimmenti and Ekker are building on zebrafish work done in collaboration with Shawn Burgess, Ph.D., at the National Human Genome Research Institute in Bethesda, Maryland.

They hope to evaluate drugs that could safeguard hearing during cancer treatment, and they’ve developed an iPad-based hearing test to allow patients to test their hearing thresholds anywhere. This is valuable, says Dr. Schimmenti, because further hearing loss can sometimes be prevented if detected early. This test is currently being validated.

From hearing to mitochondria to cancer, these silver and blue fish, decorated with glittery bands of scales, can help with an astonishing range of research questions. And the translation of that research into new diagnostic tools, medicines and treatments will be the biggest catch for patients with unmet medical needs.

-  November 22, 2017

The post Science Saturday: The fish farm appeared first on Mayo Clinic News Network.

Instead of sticking with a traditional textbook curriculum in Lincoln K-8 school in Rochester, Minn., the Mayo team collaborated with the school system to introduce a research laboratory approach using live zebrafish as a tool and focal point. The data show that first school became the top science middle school in Minnesota. Since then, the approach has been replicated in multiple grade levels in schools in other systems and states, and has been exported in a partnership with India.

MEDIA CONTACT: Bob Nellis, Mayo Clinic Public Affairs, 507-284-5005, Email: newsbureau@mayo.edu.

“These analyses provide evidence that scientifically rigorous evaluation demonstrating relevant program efficacy is indeed achievable in education science,” says Joanna Yang, a Ph.D. candidate in Clinical and Translational Sciences at Mayo Graduate School and first author of the article.

The study follows the growth of 4 cohorts of participating students assessed for proficiency in science in grades 5 and 8. Outcomes from students employing InSciEd Out curriculum are compared to cohorts at the district and state level following traditional curriculum. The InSciEd Out students show identity of scientists through a more than 8-fold increase in science fair participation. They show entry into the scientific pipeline through a doubling in their choice to enter advanced science classes when transitioning to high school. Each of these changes is shown in the manuscript to be sustained for 6 years in the science/education partnership.

InSciEd Out launched as a collaboration among Mayo Clinic, Winona State University-Rochester, and Rochester Public Schools in 2009. It has since grown to include collaborations in Minneapolis and St. Paul, Minn., Florida, Illinois, India, and Ghana. Founding partners Chris Pierret, Ph.D., Stephen Ekker, Ph.D., and James Sonju (principal at Lincoln K-8) realized that students were hungry for science and capable of much more than was currently offered. A pilot program grew into a transferrable multi-year curriculum that led to students publishing as co-authors on research papers and to a visit to the White House where the students and their mentors were praised by President Obama.

“We consider this paper to be a call to apply the same scientific rigor and clinical trial temperament (that we use in science) to education efforts,” says corresponding author Dr. Chris Pierret. “Statistical significance of findings is and should remain the gold standard for describing success.”

Co-authors include Thomas LaBounty of LaBounty Consulting; Woodbury, Minn.; and Stephen Ekker, Ph.D. of Mayo Clinic. The study was supported by the National Institutes of Health through the National Center for Advancing Translational Sciences; the National Science Foundation; and Mayo Clinic.

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Here's the podcast: Mayo Clinic Radio PODCAST March 7 2015

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Stay active to keep fit. That can be difficult for people with spinal stenosis, a condition that causes serious back pain. On the next Mayo Clinic Radio, orthopedic surgeon Dr. Paul Huddleston explains how spinal stenosis is treated.

Also on the program, Dr. Stephen Ekker discusses how the tiny zebrafish is helping to uncover treatments for everything from nicotine dependence to hearing loss. And we'll have the latest on recurring fever in children from Mayo Clinic pediatrician Dr. Thomas Boyce.

Myth or Matter-of-Fact: If I haven’t had back problems by middle age, I’m not likely to have them when I get older.

Mayo Clinic Radio is available on iHeart Radio.

Click here to listen to the program on Saturday, March 7, at 9:05 a.m., and follow #MayoClinicRadio.

To find and listen to archived shows, click here.

Mayo Clinic Radio is a weekly one-hour radio program highlighting health and medical information from Mayo Clinic. The show is taped for rebroadcast by some affiliates.

The post MAYO CLINIC RADIO appeared first on Mayo Clinic News Network.

Miss the program?  Here's the podcast:  Mayo Clinic Radio PODCAST March 7 2015

Myth or Matter-of-Fact: If I haven’t had back problems by middle age, I’m not likely to have them when I get older.

To listen to the program at 9 a.m. Saturday, March 7, click here.

Follow #MayoClinicRadio and tweet your questions.

Mayo Clinic Radio is available on iHeartRadio.

Mayo Clinic Radio is a weekly one-hour radio program highlighting health and medical information from Mayo Clinic.

To find and listen to archived shows, click here.

The post Mayo Clinic Radio: Spinal Stenosis/Zebrafish/Recurring Fever appeared first on Mayo Clinic News Network.