Category Archives: Genetic medicine

Scientists at the Casey Eye Institute, in Portland, Ore., have have injected a harmless virus containing CRISPR gene-editing instructions inside the retinal cells of a patient with a rare form of genetic blindness. KTSDesign/Science Photo Library/Getty Images hide caption

Scientists at the Casey Eye Institute, in Portland, Ore., have have injected a harmless virus containing CRISPR gene-editing instructions inside the retinal cells of a patient with a rare form of genetic blindness.

For the first time, scientists have used the gene-editing technique CRISPR to try to edit a gene while the DNA is still inside a person's body.

The groundbreaking procedure involved injecting the microscopic gene-editing tool into the eye of a patient blinded by a rare genetic disorder, in hopes of enabling the volunteer to see. They hope to know within weeks whether the approach is working and, if so, to know within two or three months how much vision will be restored.

"We're really excited about this," says Dr. Eric Pierce, a professor of ophthalmology at Harvard Medical School and director of the Inherited Retinal Disorders Service at Massachusetts Eye and Ear. Pierce is leading a study that the procedure launched.

"We're helping open, potentially, an era of gene-editing for therapeutic use that could have impact in many aspects of medicine," Pierce tells NPR.

The CRISPR gene-editing technique has been revolutionizing scientific research by making it much easier to rewrite the genetic code. It's also raising high hopes of curing many diseases.

Before this step, doctors had only used CRISPR to try to treat a small number of patients who have cancer, or the rare blood disorders sickle cell anemia or beta-thalassemia. While some of the initial results have been promising, it's still too soon to know whether the strategy is working.

In those other cases, doctors removed cells from patients' bodies, edited genes in the cells with CRISPR in the lab and then infused the modified cells back into the volunteers' bodies to either attack their cancer or produce a protein their bodies are missing.

In this new experiment, doctors at the Casey Eye Institute in Portland, Ore., injected (into the eye of a patient who is nearly blind from a condition called Leber congenital amaurosis) microscopic droplets carrying a harmless virus that had been engineered to deliver the instructions to manufacture the CRISPR gene-editing machinery.

Beginning in infancy, the rare genetic condition progressively destroys light-sensing cells in the retina that are necessary for vision. Vision impairment with LCA varies widely, but most patients are legally blind and are only able to differentiate between light and dark or perhaps to detect movement.

"The majority of people affected by this disease have the most severe end of the spectrum, in terms of how poor their vision is," Pierce says. "They're functionally blind."

The goal is that once the virus carrying the CRISPR instructions has been infused into the eye, the gene-editing tool will slice out the genetic defect that caused the blindness. That would, the researchers hope, restore production of a crucial protein and prevent the death of cells in the retina, as well as revive other cells enabling patients to regain at least some vision.

"It's the first time the CRISPR gene-editing is used directly in a patient," Pierce says. "We're really optimistic that this has a good chance of being effective."

The study is being sponsored by Editas Medicine, of Cambridge, Mass., and Allergan, based in Dublin. It will eventually involve a total of 18 patients, including some as young as ages 3 to 17, who will receive three different doses.

"We're very excited about this. This is the first time we're doing editing inside the body," says Charles Albright, the chief scientific officer at Editas.

"We believe that the ability to edit inside the body is going to open entire new areas of medicine and lead to a whole new class of therapies for diseases that are not treatable any other way," Albright says.

Francis Collins, director of the National Institutes of Health, calls the advance "a significant moment."

"All of us dream that a time might be coming where we could apply this approach for thousands of diseases," Collins tells NPR. "This is the first time that's being tried in a human being. And it gives us hope that we could extend that to lots of other diseases if it works and if it's safe."

Pierce, Albright and others stressed that only one patient has been treated so far and that the study, still at a very early stage, is designed primarily to determine whether injecting the gene-editing tool directly into the eye is safe.

To that end, the researchers are starting with lowest dose and the oldest patients, who have already suffered extensive damage to their vision. And doctors are only treating one eye in each patient. All of those steps are being taken in case the treatment somehow backfires, causing more damage instead of being helpful.

"CRISPR has never been used directly inside a patient before," Pierce says. "We want to make sure we're doing it right."

Still, he says, if the underlying defect can be repaired in this patient and others with advanced damage, "we have the potential to restore vision to people who never had normal vision before. It would indeed be amazing."

The study involves a form of Leber congenital amaurosis known as Type 10, which is caused by a defect in the CEP290 gene.

If the approach appears to be safe and effective, the researchers will start treating younger patients.

"We believe children have the potential to have the most benefit from their therapy, because we know their visual pathways are still intact," Albright explains.

The procedure, which takes about an hour to perform, involves making tiny incisions that enable access to the back of the eye. That allows a surgeon to inject three droplets of fluid containing billions of copies of the virus that has been engineered to carry the CRISPR gene-editing instructions under the retina.

The idea is that once there, the CRISPR editing elements would snip out the mutation that causes a defect in CEP290. The hope is that this would be a one-time treatment that would correct vision for a lifetime.

If it works, the volunteers in the study might be able to have the procedure repeated on the other eye later.

"If we can do this safely, that opens the possibility to treat many other diseases where it's not possible to remove the cells from the body and do the treatment outside," Pierce says.

The list of such conditions might include some brain disorders, such Huntington's disease and inherited forms of dementia, as well as muscle diseases, such as muscular dystrophy and myotonic dystrophy, according to Pierce and Albright.

"Inherited retinal diseases are a good choice in terms of gene-based therapies," says Artur Cideciyan, a professor of ophthalmology at the University of Pennsylvania, given that the retina is easily accessible.

But Cideciyan cautions that other approaches for these conditions are also showing promise, and it remains unclear which will turn out to be the best.

"The gene-editing approach is hypothesized to be a 'forever fix,' " he says. "However, that's not known. And the data will have to be evaluated to see the durability of that. We'll have to see what happens."

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The Mercer Island School District will present its fifth annual Pathfinder Awards to Robin Bennett and Steve Hawes.

The Pathfinder Award is the districts highest alumni honor, presented to graduates of Mercer Island High School (MIHS) whose achievements, strength of character, and citizenship inspire and challenge todays youth to make significant contributions to humankind.

Bennett, Class of 1977

Inspired by her MIHS biology teacher Bill Tougaw, Bennett graduated from Kenyon College and was among the first graduates from the genetic counseling training program at Sarah Lawrence College.

She began her career at the University of Washington Medical Center as its first certified genetic counselor, where she continues to work 35 years later as senior genetic counselor and manager of the Genetic Medicine Clinic. The clinic has grown into one of the leading clinics in the country for adult and cancer genetics services.

Bennett is a leader in developing genetic counseling practice recommendations, including the criterion for a genetic family history that are now the world standard. Her book, The Practical Guide to the Genetic Family History (2nd edition) is used to train students around the world (the book is dedicated to Bill Tougaw).

She is a national and international leader in the field of genetic counseling and beyond, having served as president of the National Society of Genetic Counselors and on the board of directors of the major national and international societies in human genetics and genetic counseling. She is the first genetic counselor to receive a faculty title in the UW School of Medicine where she now is a clinical professor. She has mentored many students who are interested in genetic counseling. Bennett is the acting director of the new Masters in Genetic Counseling Program being developed in the University of Washington School of Medicine.

Hawes, Class of 1968

Nearly 52 years after he graduated, Steve Hawes name remains etched throughout the record book of the MIHS boys basketball program.

The MIHS records include most points in a game (49), most rebounds in a game (40), career rebounds, rebounds in a season and rebounds per game. He averaged 28 points per game and 20 rebounds per game in his senior season, 1967-68, which was also the first year for hall of fame coach Ed Pepple.

Hawes went on to star for four years at the University of Washington, averaging 20 points and 13 rebounds a game over his career and was later inducted into the Husky Hall of Fame and the Pacific-10 Conference Hall of Honor. Hawes was selected in the second round of the 1972 NBA draft, but chose first to play overseas in Italy. He began his NBA career in 1974 with the Houston Rockets, then played one season with Portland and seven with Atlanta before finishing his career with the hometown Seattle SuperSonics in 1983 and 1984. He returned to Italy for one final season before retiring as a player.

Hawes came home again to Seattle, serving as an assistant coach at Seattle Pacific, Seattle University and UW. He started coaching high school basketball while operating Advent Print Resources, which he sold in 2013 after 20 years. He is now in his third stint as the boys basketball coach at The Bush School.

Event

The newest Pathfinders will be honored at the Mercer Island Schools Foundations Breakfast of Champions on April 28. Register to attend the breakfast online at mercerislandschoolsfoundation.com.

A permanent Pathfinder Awards wall has been created at Mercer Island High School alongside previously recognized distinguished graduates. Seventeen (17) alumni have now been recognized since the awards began in 2016.

The recipients were selected from dozens of nominations submitted by the community at large and chosen by a selection committee comprised of staff, students, administrators, community members and alumni from the district and the Mercer Island Schools Foundation.

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March 04, 2020 -Massachusetts General Hospital (MGH) is launching a new Preventive Genomics Clinic that will help advance precision medicine and preventive care by leveraging genetic information.

The new clinic will be integrated with the primary care practices at MGH, and will aim to help patients better understand, prevent, and predict disease. MGH chose to establish the genomics clinic after receiving requests from providers and patients for greater use of genetics in clinical care.

We believe DNA testing will be a key piece of routine care in the future, said Amit V. Khera, MD, an MGH cardiologist and co-founder of the new clinic. But, in many cases, our PCPs were unsure which of the available genetic tests were most appropriate for their patients or how best to integrate that information into an individualized screening or treatment plan. Thats why it was so important for us to root ourselves within primary care from the start.

Common reasons for referral to the clinic include requests for interpretation of an existing genetic test result, concern about family history of disease, or an interest in learning about the risks and benefits of testing while still asymptomatic.

Patients meet with a genetic counselor and physician to gather personal and family history information. If patients do decide to proceed with genetic testing, the team reviews testing options, works with the patients health insurance to determine whether it would be covered, and coordinates with the patients care team to make a plan based on test results.

READ MORE: FDA Approvals Advance Precision Medicine, Genomics Treatments

What has been surprising is the majority of the tests weve ordered have been fully covered by medical insurance based on family history or other indications, said Renee Pelletier, lead genetic counselor of the new program. This speaks to the underutilization of appropriate genetic testing for our patients.

For patients who are truly asymptomatic and have no family history of disease, the clinic offers preventive genomics assessments that typically arent covered by insurance. This could include testing for the BRCA1 mutations, which signal very high risk for breast and ovarian cancer, as well as mutations that can lead to high cholesterol levels and risk for early heart attack. In both of these cases, treatment options exist that can help patients overcome these genetic risks.

The team has also launched an eConsult program, which allows any physician to request a review of his or her patients medical record by the Preventive Genomics Clinic. Staff at the clinic can then determine whether genetic testing or a clinic appointment would be beneficial for the patient. Additionally, the team can answer questions about ordering new genetic testing or interpreting prior genetic testing results.

In many cases, we are able to answer a key clinical question just based on review of medical records, said Leland Hull, MD, a primary care physician in the group. For others, we recommend they be seen in our clinic or one of the several subspecialty clinics available at MGH for more detailed evaluation.

In the future, the clinic expects to see patients who learn about high genetic risk from ongoing research studies, including the Partners HealthCare Biobank or the NIH All of Us Research Program. Over the next several years, these programs are expected to perform sequencing of more than 100,000 participants in the Boston area.

READ MORE: New Precision Medicine Program to Study Role of Genomics in Disease

As the healthcare industry has increasingly recognized the important role precision medicine and genomics can play in patient health, more organizations are supporting the integration of genetic testing with routine clinical care.

Recently, a group of stakeholders launched the Institute for Gene Therapies (IGT), which will aim to modernize the US regulatory and reimbursement framework to ensure gene therapies for patients who need them.

The incredible scientific advancements in this space present unique opportunities to directly improve and save the lives of patients suffering from debilitating diseases, said IGT Chairman and former Congressman Erik Paulsen.

This is not some far-off future patients are already benefiting from the first FDA-approved gene therapies. But we need policy to move faster toward this new reality where we can treat the causes of many diseases. The Institute for Gene Therapies and our members believe unique regulatory and reimbursement structures need to be established, novel development pathways need to be embraced and new value-based arrangements need to be tested.

With the launch of the Preventive Genomics Clinic, MGH will help further incorporate novel tests and treatments into everyday healthcare delivery.

Its exciting to know we can now support access to genomics long before disease develops, promoting the best outcomes for our patients, said Heidi Rehm, PhD, chief genomics officer at MGH. Our goal is to build this resource for our own community and collaborate with other hospitals across the country in defining the best models for this new type of preventive clinical care.

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New Genomics Clinic Will Enable Preventive Care, Precision Medicine - HealthITAnalytics.com

University of Georgia senior Callan Russell, an Honors student from McDonough, has been selected for the third cohort of Knight-Hennessy Scholars, a global graduate-level program at Stanford University.

Established in 2016, the Knight-Hennessy Scholars program provides full funding for graduate students as they pursue studies ranging from medicine to law to doctoral programs as well as joint and dual degrees.

The program is designed to prepare students to take leadership roles in finding creative solutions to complex global issues.

Callan is a very active Honors student who has been selected for some of our most impressive scholarships and programs, including the Crane Leadership Scholarship, said David S. Williams, associate provost and director of the Honors Program. Callan has also been greatly engaged with undergraduate research through CURO, which has positioned her to enter a most exciting new field, genetic counseling. Given that Stanford has arguably the top program in this cutting-edge area, the Knight-Hennessy Scholarship is a perfect fit for her.

Callan Russell. (Photo by Stephanie Schupska)

Russell will graduate in May with a bachelors degree in genetics and a minor in music and will begin a masters degree in human genetics and genetic counseling at Stanford University this September. Her long-term goal is to be a prenatal genetic counselor in a hospital setting, educating potential parents about their family histories and the role genetics play in family planning.

Genetic counseling combines hard science with caring for people and the opportunity to directly interact with patients, Russell said. Stanford, the Knight-Hennessy Scholars program, and the niche they provide are a dream fit for my career goals.

For the past two years, Russell has conducted genetics research in the lab of Robert Schmitz, Lars G. Ljungdahl Distinguished Investigator in the Franklin College of Arts and Sciences. A CURO research assistant, she has been studying heat tolerance and photomorphogenesis in Arabidopsis thaliana, a small flowering plant widely used as a model organism in genetics and plant biology. She also spent six weeks last summer shadowing genetic counselors through the University of South Carolinas School of Medicine.

Russell is band captain and trombone section leader in both the UGA Redcoat Marching Band and various UGA ensembles and coordinates community and university events. She volunteers with Extra Special People, assisting children and adults with disabilities; co-founded UGA G.E.N.E.S., the first genetics club at UGA; and has presented her Arabidopsis research at the CURO Symposium. She also received the Vince Dooley Redcoat Band Scholarship.

UGAs major scholarships coordinator, housed in the Honors Program, provides students from across campus with assistance as they apply for national, high-level scholarships. For more information, contact Jessica Hunt at 706-542-6206 or jhunt@uga.edu.

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Callan Russell named a Knight-Hennessy Scholar - University of Georgia

To examine genetic associations with food preferences, researchers from the Riken Center for Integrative Medical Sciences (IMS) and Osaka University in Japan studied the genetic data and food preferences of more than 160,000 people in Japan.

The research, published in the journal Nature Human Behavior, found genetic links for 13 dietary habits including consumption of alcohol, other beverages and foods, and also complex human diseases such as cancer and diabetes.

"We know that what we eat defines what we are, but we found that what we are also defines what we eat," said Yukinori Okada, Senior Visiting Scientist at Riken IMS and professor at Osaka University, in a press release.

This involves grouping thousands of people together depending on whether they have a disease and looking at DNA markers called single nucleotide polymorphisms, or SNPs, which can be used to predict the presence of that disease. If researchers find a SNP that is repeatedly associated with the disease group, they can assume that people with that genetic variation might be at risk for the disease.

Rather than looking at diseases, the Riken team examined dietary habits to find out if there were any markers that made people "at risk" for typically eating certain foods.

The researchers used data of more than 160,000 Japanese people from the BioBank Japan Project, launched in 2003 with a goal to provide evidence for the implementation of personalized medicine. The project collects DNA and clinical information, including items related to participants' lifestyles such as dietary habits, which were recorded through interviews and questionnaires.

They found nine genetic locations that were associated with consuming coffee, tea, alcohol, yogurt, cheese, natto (fermented soy beans), tofu, fish, vegetables and meat.

Variants responsible for the ability to taste bitter flavors were also observed. This association was found among people who liked to eat tofu; while those without the variant consumed less alcohol or none at all.

Those who ate more fish, natto, tofu and vegetables had a genetic variant that made them more sensitive to umami tastes, best described as savory or "meaty" flavors.

The main ingredients of the foods mattered, too -- for example, there were positive genetic correlations between eating yogurt and eating cheese, both milk-based foods.

In order to find whether any of these genetic markers associated with food were also linked with disease, the researchers conducted a phenome study.

The phenome comprises all the possible observable traits of DNA, known as phenotypes. Six of the genetic markers associated with food were also related to at least one disease phenotype, including several types of cancer as well as type 2 diabetes.

Nature vs. nurture: Food edition

Since the research studied only people native to Japan, the same genetic variations associated with food preferences are likely not applicable to populations across the globe. However, similar links have been discovered in different groups.

The study authored by Okada also didn't measure environmental factors. Our environment, demographics, socioeconomic status and culture -- such as whether we eat food from work or home; our age; how much money we make; and what our families eat -- are some of the biggest drivers of our food choices.

"These factors would weigh more than the genetics in some cases," said Dr. Jos Ordovs, director of Nutrition and Genomics at Tufts University in Massachusetts, who was not involved in the study.

"Something that sometimes we have felt is that the nutrition field has been focusing too much on nutrients rather than on foods," Ordovs said.

"Previous studies have been looking at genes that were associating with higher protein intake or higher fat intake or higher carbohydrate intake," Ordovs said. "But this study is more aligned with the fact that people eat foods. They don't just eat proteins, carbohydrates and fats. People tend to eat within a specific pattern."

Further research is needed to explain an exact balance between genetic predisposition and volition when it comes to food choices in different groups of people, but Okada suggests that by "estimating individual differences in dietary habits from genetics, especially the 'risk' of being an alcohol drinker, we can help create a healthier society."

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Prefer tea over coffee? It could be your genes, study finds - CNN

By Medicine Hat News on March 3, 2020.

The province will cover the cost of another drug for Albertans with cystic fibrosis.

Effective March 1 the drug kalydeco is part of the governments drug plan.

Since 2014 kalydeco has been available to patients more than six years old who had cystic fibrosis and one specific genetic mutation. The coverage is now expanded to include an additional eight genetic mutations: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N and S549R.

Patients over 18 with an R117H mutation in the CFTR gene will also be covered for this medication.

Cystic fibrosis is a genetic disease affecting the digestive system and lungs primarily. The severity of the disease differs from person to person and it is often fatal.

The government said the pan-Canadian Pharmaceutical Alliance was able to negotiate a pricing agreement with the manufacturer of this prescription drug that made expanded coverage possible.

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Iridescent blue-striped zebrafish dart back and forth in tiny tanks stacked floor-to-ceiling in the basement of the Baylor College of Medicine. The freshwater minnowssome 13,000 strong in their watery studio apartmentsplay an integral role in innovative biomedical research.

They are part of the Gorelick Lab, one of more than 3,250 sites in 100 different countries using zebrafish to advance medicine and better understand human diseases. Led by Daniel Gorelick, Ph.D., assistant professor in the department of cellular and molecular biology at Baylor, the lab studies zebrafish to learn how certain hormones and chemicals affect the development and function of the human heart and brain, as well as other tissues.

Gorelick in the lab.

Although science and technology are constantly evolving, zebrafish have remained relevant research tools for almost 50 years. Today, scientists are harnessing the power of CRISPR-Cas9 technologywhich can edit segments of the genome by deleting, inserting or altering sections of the DNAto generate specific mutations in zebrafish.

This has been a huge advance because it allows us to create mutant strains of zebrafish that have the same mutations as are found in a human disease, said Gorelick, whose lab is housed in Baylors Center for Precision Environmental Health and is currently undergoing an expansion to accommodate as many as 30,000 fish.

In addition, scientists have long sought to map the cell-by-cell progression of animals, in pursuit of understanding how a single cell develops into trillions of cells that make up an intricate biological system of organs. With single-cell RNA sequencing, a technology named Science magazines 2018 Breakthrough of the Year, scientists are able to track the different, intricate stages of embryo development in unprecedented detail, allowing researchers like Gorelick to study the cascading effects at the cellular level.

Theres just so much evidence now that a lot of the drugs that are effective in humans are also effective in [zebrafish], so people are now starting to use fish to discover drugs, Gorelick said. You want to know, if youre taking a drug or youre exposed to some pollutant, does that cause birth defects? How does that affect the life of humans? We can use [zebrafish] as research tools to understand how the chemicals normally work in a normal embryo.

Regenerative heartZebrafish are named for the colorful horizontal stripes on their bodies, and can grow from 1.5 to 2 inches in length. The tropical fish are native to South Asia.

On the surface, zebrafish appear nothing like humans, but 70 percent of the genes in humans are found in zebrafish and 84 percent of human genes associated with human disease have a zebrafish counterpart, studies show.

George Streisinger, an American molecular biologist and aquarium enthusiast, pioneered the use of zebrafish in biomedicine at the University of Oregon in 1972. His breadth of knowledge about zebrafish laid the groundwork for research methodologies, including developing breeding and care standards and creating tools for genetic engineering and analysis. He performed one of the first genetic screens of zebrafish by using gamma rays to randomly mutate the DNA of certain zebrafish and identify offspring that had notable phenotypes, such as pigmentation defects.

That caused a big explosion in the field and then thats when things really took off, Gorelick said.

Zebrafish are now used as a genetic model for the development of human diseases, including cancer, cardiovascular diseases, infectious diseases and neurodegenerative diseasesto name a few. Housed down the street from Gorelicks lab, John Cooke, M.D., Ph.D., is using zebrafish to study atherosclerosis, the major cause of heart disease in the country. Although zebrafish have only one ventricle to pump blood to the heart, whereas humans have two (a left and a right ventricle), their vasculature is very similar to humans.

The zebrafish can help us in understanding the cardiovascular system, in achieving those basic insights, and in translating those basic insights towards something thats potentially useful for people, said Cooke, director of the Center for Cardiovascular Regeneration at Houston Methodist Research Institute.

Cooke hopes that studying the regenerative capabilities of the zebrafish heart will lead to new discoveries that help human patients.

You can remove 20 percent of their heart, and they can regenerate it, Cooke explained. Why is that? We want to know. There are groups that are studying that amazing regenerative capacity of the [zebrafish] heart, and those insights obtained from that work may lead us to new therapies for people to regenerate the human heart or, at least, improve the healing after a heart attack.

Watching cells migrateAlthough mice are genetically closer to humans than zebrafish, sharing 85 percent of the same genomes, zebrafish have a few key advantages for researchers.

On average, zebrafish produce between 50 to 300 eggs, all at once, every 10 days. Their rapid breeding allows scientists to quickly test the effects of genetic modifications (such as gene knockouts and gene knock-ins) on current fish, as well as ensuing generations.

In addition, zebrafish are fertilized and developed externally, meaning the sperm meets the egg in the water. This allows scientists to access the embryos more easily, as opposed to mouse embryos that develop inside the womb. In one of his research projects, Gorelick simply adds drugs to the water to see how the zebrafish are affected.

Most drugs in the water will get taken up by the embryo, Gorelick said. We add it into the water and it gets taken up the next day when theyre just one day old. All of that discovery happened in zebrafish because you can literally watch it live.

Not only do zebrafish embryos develop quickly, they are also transparent. Within two to four days, a zebrafish will develop all its major organsincluding eyes, heart, liver, stomach, skin and fins.

We can literally watch these cells migrate from different parts of the embryo, form the tube, constrict, form the hourglass, loop on itself, beat regularly and see blood flow all at the same time, Gorelick said. When theres a belly and a uterus, you dont have access. You can use things like ultrasound, like we do with humans, but you cant get down to single-cell resolution like we can with the fish.

Ultimately, zebrafish have proven to be a powerful resource for researchers. Although all zebrafish studies are confirmed in rats and mice, followed by human tissue, they constitute a significant stepping stone.

You wouldnt want to build a house only using a hammer and a screwdriver. I want a power drill and I want a band saw, Gorelick said. Fish are part of that. Theyre not a cure-all. Theyre not the only tool, but theyre an important tool.

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New construction will inspire discovery, collaboration, faculty recruitment at School of Medicine

Washington University in St. Louis will begin construction in March on an 11-story, 609,000-square-foot neuroscience research building on the School of Medicine campus. The project initially will bring together more than 100 research teams focused on solving the many mysteries of the brain and the bodys nervous system.

Washington University in St. Louis will begin construction in March on what will be one of the largest neuroscience research buildings in the country. Located on the School of Medicine campus, the 11-story, state-of-the-art research facility will merge, cultivate and advance some of the worlds leading neuroscience research.

The 609,000-square-foot facility and interconnected projects initially will bring together over 100 research teams focused on solving the many mysteries of the brain and the bodys nervous system. Those teams, comprising some 875 researchers, will come from a wide array of disciplines, including the medical schools neurology, neuroscience, neurosurgery, psychiatry and anesthesiology departments.

Washington University is one of the premier institutions in the world in neuroscience research, with faculty known for their contributions to the understanding of normal brain development, how nerve cells communicate, neuroimaging, neurological diseases such as Alzheimers disease, and surgical treatments for cerebral palsy, among other contributions, said Chancellor Andrew D. Martin. With this new building, we are able to offer the neuroscience community a central home and a laboratory environment that can inspire entirely new concepts that allow us to grasp a much deeper understanding of the brain and have a global impact on health and science.

The School of Medicine has a long history as one of the worlds foremost centers for neuroscience research, including as a leading institution in the study of Alzheimers disease. Its scientists have identified key molecules involved in sculpting nervous system development and triggers of neurodegenerative diseases, mapped connections from brain region to brain region, and developed pioneering surgical treatments for nerve injuries, among other groundbreaking discoveries.

David H. Perlmutter, MD, executive vice chancellor for medical affairs, the George and Carol Bauer Dean of the School of Medicine, and the Spencer T. and Ann W. Olin Distinguished Professor, said the new facility will open the door to bold new research initiatives and partnerships.

Understanding the brain is key to addressing some of the most devastating afflictions that affect mankind, Perlmutter said. So many of us have been touched by the inexorable decline of our loved ones due to diseases and conditions such as Alzheimers and Parkinsons, brain trauma, glioblastoma and severe mental illness, and we have learned that the development of effective therapies has proven formidable. As scientists, we believe that a deeper understanding of cognition and emotional regulation can help us address major public health problems such as obesity, substance abuse, depression and suicide.

The initiative will increase synergy and facilitate greater collaboration between scientists in the medical schools neuroscience-focused departments and researchers in related disciplines, especially those whose work requires close collaboration with neuroscientists.

This rendering shows a view from the west of the planned neuroscience research center.

Collaboration across disciplines will be key to advancing our understanding of this new frontier in medicine, Perlmutter said. For example, new studies have recognized the importance of the microbiome and its interaction with our immune system in shaping the development and function of the brain. Work on synaptic connections in the nervous system is also critical to the development of machine intelligence and socially interactive robots that could solve many of the most important challenges of modern society. This building will be dedicated to advancing our global leadership position in solving these very big problems with imagination and rigor.

The new research center also is expected to inspire health-minded entrepreneurial pursuits and synergy with visionary business developers situated within a stones throw of the new research center. The building and related construction, which will be built at an expected cost of $616 million, will sit at the eastern edge of the Medical Campus, in the 200-acre Cortex Innovation Community, one of the fastest growing business, innovation and technology hubs in the United States and home to numerous biotech startups founded by Washington University faculty, staff and students.

We are constructing the building at the intersection of Cortex and the Medical Campus to encourage efforts by Washington University neuroscientists to transform their research into innovations that can move rapidly to improve medical care and quality of life for people with neurological conditions, said Jennifer K. Lodge, PhD, the universitys vice chancellor for research.

Among Washington Universitys achievements in the field of neuroscience, two Nobel Prizes in Physiology or Medicine have been won by scientists at the university. In 1944, Joseph Erlanger and Herbert Gasser won the Nobel for their work studying nerve fibers. They showed that the conduction velocity of nerve impulses is faster in thick nerve fibers than in thin fibers, and identified numerous other properties of sensory and motor nerves. And in 1986, Stanley Cohen and Rita Levi-Montalcini won the Nobel for discovering chemical growth factors essential for cell growth and development in the body. In the 1950s, they discovered nerve growth factor, a protein crucial for building networks of nerves.

The School of Medicine has a longtime, deep commitment to understanding, treating and preventing Alzheimers in particular. In the U.S., 5.8 million people are living with the disease, with the number projected to rise to nearly 14 million by 2050. Alzheimers and other dementias cost the U.S. a staggering $290 billion in 2019, and the cost is predicted to climb as high as $1.1 trillion by 2050, according to the Alzheimers Association.

The new center is intended to complement and build on The Brain Research Advancing Innovative Neurotechnologies Initiative (The BRAIN Initiative), an extensive effort launched in 2013 by the National Institutes of Health (NIH) to revolutionize our understanding of the brain and brain disorders. Despite tremendous advances in neuroscience, the causes of numerous neurological and psychiatric conditions remain unknown. Like The BRAIN Initiative, Washington Universitys leadership understands how critical that information will be to figuring out how to effectively counter these diseases and help the many people suffering from them. In fact, several research projects led by Washington University investigators are funded by The BRAIN Initiative and will find a home in the new neuroscience building.

The medical schools faculty have long been lauded for the collaborations they develop across the university, and the new research facility is intended to boost and significantly drive such efforts. The building will feature research neighborhoods and a shared area on each floor to spur conversation and collaboration. The neighborhoods will be organized around research themes among them, addiction, neurodegeneration, sleep and circadian rhythm, synapse and circuits, and neurogenomics and neurogenetics that bring together people with common interests from multiple departments. The first researchers are slated to move into the building in 2023. While the initial construction will accommodate more than 100 research teams, additional shell space could be built out later for another 45 research teams.

This rendering shows a view from the southwest of the planned neuroscience research building.

The additional space created in this building represents the next step in the schools strategic plan to increase its research base by more than 30% over the next 10 years. The school is currently ranked fourth among U.S. medical schools in NIH funding and aims to leverage the breadth of its basic and clinical research assets, together with existing and new industry partnerships, to enhance its core mission in discovery and development of new treatments.

We have been very successful at attracting top-notch researchers and their teams to the School of Medicine, and this continues to be a chief goal, Perlmutter said. The focus on neuroscience in this building is also integral to our aspirations across the Medical Campus to utilize the paradigm of personalized medicine and to address the problems of aging and degenerative diseases.

Added David Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology: A key goal for the neuroscience center is to take what we discover in our laboratories and get it out into the public sector so patients, and society as a whole, can benefit. This building and the collaborations it will grow will position us to achieve meaningful breakthroughs in science and medicine.

An internationally renowned expert on the causes of Alzheimers disease, Holtzman and his team helped develop antibodies aimed at preventing dementia by reducing deposits of the Alzheimers proteins amyloid beta and tau in the brain, and have advanced the understanding of how sleep and apolipoprotein E the most important genetic risk factor for Alzheimers contribute to brain injury. Holtzman also is involved in a project led byRandall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology, to develop a blood test that can measure levels of amyloid beta and other proteins in the blood with the goal of diagnosing Alzheimers before symptoms develop.

The new neuroscience facility to be located at 4370 Duncan Avenue extends the School of Medicines reach eastward. As part of the construction, the university will add to its network of elevated, connected walkways, known as the Link, to reach the neuroscience research hub, and also will build a utility plant. In addition to the facilitys labs and research-focused areas, the new building will have event space, a large seminar room and a food-service area, as well as an 1,860-space parking garage. The architectural firms Perkins and Will, and CannonDesign are the projects designers, and McCarthy Building Companies will oversee construction.

Neuroscience research is a synergetic enterprise that depends on the expertise of people in many fields, Holtzman said. By bringing together so much knowledge, talent and passion, this new facility will make it considerably more likely that people will have the kinds of water-cooler discussions that lead to interdisciplinary game-changing ideas and projects. Im very excited to see what we will do.

Neuroscience research highlights

Washington University researchers:

Through ongoing research, they are:

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Washington University to break ground on major neuroscience research hub Washington University School of Medicine in St. Louis - Washington...

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A unique molecular structureevident in induced pluripotent stem cells taken from people with young-onset Parkinson's diseasesuggests that the defects may be present throughout patients' lives, and that they could therefore be used as diagnostic markers.

Induced pluripotent stem cells (iPSCs) taken from patients with young-onset Parkinson's disease (YOPD) and grown into dopamine-producing neurons displayed a molecular signature that was corrected in vitro, as well as in the mice striatum, by a drug already approved by the US Food and Drug Administration (FDA), a study published in the January 27 online edition of Nature Medicine found.

Although the patients had no known genetic mutations associated with PD, the neurons grown from their iPSCs nonetheless displayed abnormally high levels of soluble alpha-synucleina classic phenotype of the disease, but one never before seen in iPSCs from patients whose disease developed later in life. Surprisingly, for reasons not yet understood, the cells also had high levels of phosphorylated protein kinase C-alpha (PKC).

In addition, the cells also had another well-known hallmark of PD: abnormally low levels of lysosomal membrane proteins, such as LAMP1. Because lysosomes break down excess proteins like alpha-synuclein, their reduced levels in PD have long been regarded as a key pathogenic mechanism.

When the study team tested agents known to activate lysosomal function, they found that a drug previously approved by the FDA as an ointment for treating precancerous lesions, PEP005, corrected all the observed abnormalities in vitro: it reduced alpha-synuclein and PKC levels while increasing LAMP1 abundance. It also decreased alpha-synuclein production when delivered to the mouse striatum.

Unexpectedly, however, PEP005 did not work by activating lysosomal function; rather, it caused another key protein-clearing cellular structure, the proteasome, to break down alpha-synuclein more readily.

The findings suggest that the defects seen in the iPSCs are present throughout patients' lives, and that they could therefore be used as diagnostic markers. Moreover, the drug PEP005 should be considered a potentially promising therapeutic candidate for YOPD and perhaps even for the 90 percent of PD patients in whom the disease develops after the age of 50, according to the study's senior author, Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and professor of biomedical sciences and medicine at Cedars-Sinai.

These findings suggest that one day we may be able to detect and take early action to prevent this disease in at-risk individuals, said study coauthor Michele Tagliati, MD, FAAN, director of the movement disorders program and professor of neurology at Cedars-Sinai Medical Center.

But the study still raises questions regarding the biological mechanisms, and certainly does not warrant off-label prescribing of PEP005 at this time, said Marco Baptista, PhD, vice president of research programs at the Michael J. Fox Foundation, who was not involved with the study.

Repurposing PEP005 is a long way away, Dr. Baptista said. This is not something that neurologists should be thinking about prescribing or recommending to their patients.

Accumulation of alpha-synuclein has been seen in iPSC-derived dopaminergic cultures taken from patients with known genetic defects, but such defects account for only about 10 percent of the PD population. In those without known mutations, on the other hand, no defects in iPSC-derived dopamine-producing neurons have been seen. Until now, however, such studies had been conducted only in patients who had developed PD after age 50.

My idea was why to look in young-onset patients, said Dr. Svendsen.

The idea paid off more richly than he expected. We were shocked to find a very, very prominent phenotype, a buildup of alpha-synuclein, in the neurons of these patients who are genetically normal, Dr. Svendsen said. None of the controls had a buildup of synuclein, and all but one of the early PD patients had a twofold increase in it.

The signature is so consistent, he said, that it offers a natural model that can be interrogated to further understand its workings.

Because high levels of PKC were also seen, Dr. Svendsen said, We picked a bunch of drugs known to reduce PKC. We found one, PEP005, which is actually extracted from the milkweed plant, and it completely reduced synuclein levels almost to normal in dopaminergic neurons. And it also increased dopamine levels in those cells, so we got two for one.

After observing the effects of PEP005 in vitro, We put it into the mouse brain and found it reduced synuclein in vivo, Dr. Svendsen said. But we had to infuse it right into the brain. We're now trying to work out how to get it across the blood-brain barrier more efficiently.

To determine how PEP005 lowers cellular levels of alpha-synuclein, his group tested whether it was activating the lysosome, but found to their surprise that it did not do this until after the synuclein had already been degraded.

Then we asked whether it could be the proteosome, which also breaks down proteins but normally doesn't break down synuclein, Dr. Svendsen said. But when we applied PEP005, it did activate the proteasome. So we think that might be the mechanism.

Because the drug is currently applied externally, Dr. Svendsen said, the next step will be to see if it crosses the blood-brain barrier when applied to the skin of mice, and whether that results in a lowering of synuclein levels in dopaminergic neurons.

Justin Ichida, PhD, the Richard N. Merkin assistant professor of stem cell biology and regenerative medicine at the USC Keck School of Medicine, said the findings are quite important in the field. The potential diagnostic tools they made could be important in clinical care. And identifying a drug that may very effectively reverse the disease in neurons is a very important discovery.

He wondered, however, whether the increase in alpha-synuclein is truly specific to Parkinson's neurons or if it would also be seen in iPSC neurons from patients with Alzheimer's disease or amyotrophic lateral sclerosis.

I wonder if alpha-synuclein accumulating is a sign of PD in a dish or is a consequence of neurodegeneration or impaired protein degradation in general, Dr. Ichida said. That's a key question if you want to use this molecular signature as a diagnostic tool.

He also questioned if proteins other than alpha-synuclein, such as tau, would also be seen to accumulate in the iPSCs of YOPD patients.

If one of the protein-clearance mechanisms in the cell is working poorly, you would imagine that other things would also accumulate, Dr. Ichida said.

In response, Dr. Svendsen said that while some proteins other than alpha-synuclein were reported in the paper at increased levels, We did not look at tau specifically, but are in the process of looking right now. It could be that synuclein and some other proteins are somehow altered to evade them from being degraded by the lysosome, or that there is a general lysosomal problem.

Patrik Brundin, MD, PhD, director of the Center for Neurodegenerative Science and Jay Van Andel Endowed Chair at Van Andel Research Institute in Grand Rapids, MI, called the paper very interesting and thought-provoking. If these findings hold up, they could shift our understanding of young-onset PD. They imply that there is a strong genetic component that has not been picked up in prior genetic studies.

Dr. Brundin said he would like to see the results replicated in another lab using different sets of reagents. It is so intriguing and rather unexpected that one wonders if the observations really apply, as the study states, to 95 percent of all YOPD.

He also questioned whether all the young-onset PD patients are similar. Clearly the iPSCs studied here are not monogenetic PD, so they must be very diverse genetically and still all have the same alpha-synuclein change.

Dr. Brundin also asked why the abnormalities seen in YOPD neurons have not previously been seen in older cases of PD. Is there a specific cutoff regarding age-of-onset when these purposed genetic differences apply? he asked.

Dr. Svendsen responded: We don't know why the YO have this phenotype or exactly what the cut off is. We have, however, looked at one adult-onset case that did not show this phenotype. Also, one of our YO cases did not show this phenotype. Thus some patients even with early onset may not have it. We are currently testing many more cases from older-onset patients.

Dr. Brundin also wanted to know whether non-dopaminergic neurons have the same deficits described in the study.

We don't know which neurons specifically have the protein deficit as we cannot do single-cell proteomics, Dr. Svendsen answered. It could be a little in all cells or a lot in a small set. Immunocytochemistry is not quantitative but showed that it is more likely a general increase in synuclein and not specific to dopaminergic neurons.

While the findings in iPSCs suggest that the abnormal levels of alpha-synuclein must be present at birth, Dr. Brundin said, I do not know how to reconcile the present findings with genetic data.

The absence of previously described mutations in the YOPD patients means only that more work must be done to uncover the genetic underpinnings, Dr. Svendsen said.

We're just at the tip of the iceberg with understanding the genome, he said. It's such a bizarrely complex beast. Perhaps there are a thousand different proteins interacting to stop the synuclein from being degraded. In 10 years, we probably will be clever enough to see it. We know it must be there. Now the genome guys will go after it.

Dr. Baptista from the Michael J. Fox Foundation said he agreed with the view that there must be genetic alterations underpinning the defects seen in the iPSCs.

Just because we call something non-genetic could simply reflect the current ignorance of the field, he said. I think the discoveries are simply difficult to make.

He added that he wished that the main comparator in the study was not healthy controls, and that there were more older-onset iPSCs to compare against YOPD patients' samples.

Dr. Svendsen said it could be that the iPSCs from older-onset patients might yet be found with additional study to display abnormalities similar to those seen in YOPD.

Right now we only see it in young onset, he said. We may need to leave the cultures longer to see in the older-onset patients. We are doing those experiments now.

Drs. Tagliati and Svendsen disclosed that an intellectual patent is pending for diagnostic and drug screening for molecular signatures of early-onset Parkinson's disease. Dr. Ikeda is a co-founder of AcuraStem Inc. Dr. Brundin has received commercial support as a consultant from Renovo Neural, Inc., Lundbeck A/S, AbbVie, Fujifilm-Cellular Dynamics International, Axial Biotherapeutics, and Living Cell Technologies. He has also received commercial support for research from Lundbeck A/S and Roche and has ownership interests in Acousort AB and Axial Biotherapeutics. Dr. Baptista had no disclosures.

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Molecular Signature of Young-Onset Parkinson's Disease Is... : Neurology Today - LWW Journals

Netherton syndrome, a rare skin disease caused by a single genetic mutation, is exacerbated by the presence of two common Staphylococcal bacteria living on human skin, one of which was previously thought to only offer protective properties, report University of California San Diego School of Medicine researchers.

Our study shows how closely tied the human genome is to the genetic information in our skin microbiome. This rare disease is due to a mutation in a human gene. But, in adults, the symptoms of the disease are driven by the skin microbiome, said senior author Richard Gallo, MD, PhD, Irma Gigli Distinguished Professor and chair of the Department of Dermatology at UC San Diego School of Medicine.

The two genomes work closely together. When one is off, even by a single gene, the other genome reacts.

In a multi-institutional study published online in Cell Reports on March 3, 2020, Gallo and collaborators identified how Staphylococcus aureus and Staphylococcus epidermidis can act as a catalyst for skin inflammation and barrier damage in mouse models.

S. aureus is a pathogenic bacteria known to aggravate skin conditions, such as atopic dermatitis. When it becomes resistant to antibiotics, it is known as methicillin-resistant Staphylococcus aureus or MRSA. It is a leading cause of death resulting from infection in the United States.

Conversely, S. epidermidis is common on healthy human skin and presumed benign. In a previous study, Gallo reported that a specific strain of this bacterium seemed to hold a protective property by secreting a chemical that kills several types of cancer cells but does not appear to be toxic to normal cells. S. epidermidis was also known to promote wound repair, skin immunity and limit pathogen infections. It was not known that, in some cases, S. epidermidis can have pathogenic effects.

Netherton syndrome is a result of a mutation in the SPINK5 gene, which normally provides instructions for making a protein called LEKT1. This protein is a type of protease inhibitor.

With the loss of LEKT1, excess proteases are stimulated by Staphylococcal bacteria on people with Netherton syndrome. This protease activity leads to a breakdown of proteins and skin inflammation.

This is a major breakthrough for these patients as it describes how we can treat a human genetic mutation by targeting the microbiome, said Gallo, who is also a faculty member in the Center for Microbiome Innovation at UC San Diego. Altering bacterial gene expression is much easier than trying to fix a mutation in humans.

Researchers swabbed the skin of 10 people with Netherton syndrome and found that their skin microbiome had an abundance of certain strains of S. aureus and S. epidermidis. However, unlike the skin of normal subjects, the excess bacteria produced genes that could not be controlled due to the gene mutation in Netherton syndrome.

According to the National Institutes of Health, most people with this recessive inherited genetic disorder have immune system-related problems, such as food allergies, hay fever, asthma, or an inflammatory skin disorder called eczema. It is estimated that 1 in 200,000 newborns are affected.

In addition to demonstrating how an abnormal skin microbiome promotes inflammation in Netherton syndrome, this study provides one of the most detailed genomic descriptions to date of the skin microbiome, said Gallo.

Co-authors include: Michael R. Williams, James A. Sanford, Livia S. Zaramela, Anna M. Butcher and Karsten Zengler of UC San Diego; Laura Cau, of UC San Diego and SILAB; Shadi Khalil, of UC San Diego and University of Virginia School of Medicine; Yichen Wang and Alain Hovnanian of Imagine Institute and Universit Paris Descartes-Sorbonne Paris Cit; Drishti Kaul and Christopher L. Dupont of J. Craig Venter Institute; and Alexander R. Horswill of Department of Veterans Affairs Denver Health Care System and University of Colorado Anschutz Medical Campus.

Funding for this research came, in part, from the National Institutes of Health (R37AI052453, R01AR076082, R01AR074302 and R01AR069653) and the Atopic Dermatitis Research Network (U19 AI117673).

Disclosure: Gallo is a co-founder, scientific advisor, consultant, and has equity in MatriSys Biosciences and is a consultant, receives income, and has equity in Sente. All other authors declare no competing interests.

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Presence of Staph Bacteria in Skin Microbiome Promotes Netherton Syndrome Inflammation - UC San Diego Health