blindness
Metabolomics: A New Approach to Understanding Glaucoma
Posted on by Michael F. Chiang, M.D., National Eye Institute
Glaucoma remains one of the most common causes of vision loss and blindness in the U.S. and much of the world, disproportionately affecting older people, African Americans, and Hispanics and Latinos. Early signs of glaucoma can vary, from eye pressure to changes in the appearance of the optic nerve, and the disease can progress for years undetected while causing irreversible vision loss. More research is needed to understand the complex processes that underpin how glaucoma develops and progresses. If detected early enough, doctors can intervene and stop or slow its progression, thus preventing or minimizing vision loss.
While more than 120 genetic factors have been linked to glaucoma, these genes account for less than 10% of glaucoma cases. Scientists are exploring other ways to predict glaucoma, including studying metabolites to see if they hold any clues. These small molecules are produced by metabolism, including the breakdown of nutrients when we digest food or byproducts from the medicine we take. Identifying at-risk individuals based on their metabolic profile might present an opportunity to intercept disease before vision loss.
Researchers already use metabolites as biomarkers or indicators to help diagnose disease or assess disease risk. There’s a standard blood test called a comprehensive metabolic blood panel that doctors use to measure levels of metabolites circulating in your blood—sugars like glucose, minerals such as calcium, and proteins such as creatinine.
Your metabolome is the complete set of metabolites not in just your blood but in your entire body. National Eye Institute-funded researchers led by Louis Pasquale, Icahn School of Medicine at Mount Sinai, New York, in collaboration with Oana A. Zeleznik and Jae Hee Kang of Brigham and Women’s Hospital, Boston, recently explored 369 blood metabolites in relation to glaucoma in a large study.1
The research team examined blood that had been stored frozen from two long-term studies of health professionals: the Nurses’ Health Studies and the Health Professionals’ Follow-Up Study. They compared about 600 participants who had developed glaucoma after study enrollment to a group of similar participants who didn’t. On average, the participants who developed glaucoma did so about 10 years after their initial blood draw in the study.
The researchers found a particularly strong association between glaucoma and two classes of lipids (fats): triglycerides and diglycerides. Patients with elevated triglycerides and diglycerides were more likely to develop glaucoma, and the association was strongest in a subtype of glaucoma that causes early loss of central vision. They confirmed their findings in a cross-sectional analysis of data from the UK Biobank.
High levels of triglycerides have been linked to a variety of health problems, notably heart disease and stroke. The good news is that effective treatments to control triglyceride levels already exist. Statin drugs, for example, lower blood lipid levels. While studies looking at statin use and glaucoma risk have shown mixed results, we may learn that specific subtypes of glaucoma can be effectively controlled with statins. More research is needed to know if existing drugs might prevent glaucoma.
Pasquale’s work adds to a growing body of evidence that links health status to metabolism. Similar associations have been made between various metabolites and kidney cancer,2 pregnancy complications,3 type 2 diabetes,4 and Alzheimer’s disease.5 For researchers interested in exploring associations between metabolites and disease risk, the NIH Common Fund offers scientists a national and international repository for metabolomics data and metadata called the Metabolomics Workbench Metabolite Database, which contained more than 167,000 entries in 2022.
These findings and others offer the potential to prevent more and treat less. We urge anyone in an at-risk group, including people with a family history of glaucoma, to get regular, comprehensive eye exams.
References:
[1] OA Zeleznik, et al. Plasma metabolite profile for primary open-angle glaucoma in three US cohorts and the UK Biobank. Nature Communications DOI:10.1038/s41467-023-38466-x (2023)
[2] OO Bifarin, et al. Urine-Based Metabolomics and Machine Learning Reveals Metabolites Associated with Renal Cell Carcinoma Stage. Cancers (Basel) DOI:10.3390/cancers13246253 (2021)
[3] EW Harville, et al. Untargeted analysis of first trimester serum to reveal biomarkers of pregnancy complications: a case-control discovery phase study. Scientific Reports DOI:10.1038/s41598-021-82804-1 (2021)
[4] Nightingale Health Biobank Collaborative Group, et al. Metabolomic and genomic prediction of common diseases in 477,706 participants in three national biobanks. medRxiv DOI: 10.1101/2023.06.09.23291213 (2023). *note this article is a pre-print and is not peer-reviewed
[5] DK Barupal, et al. Sets of coregulated serum lipids are associated with Alzheimer’s disease pathophysiology. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. DOI:10.1016/j.dadm.2019.07.002 (2019)
NIH Support: National Eye Institute, National Cancer Institute
Editor’s note: This blog post was updated on Jan. 18, 2024, to include Oana A. Zeleznik as one of the collaborators.
STEM Education and Training Builds Diversity Among Next Generation of Biomedical Scientists
Posted on by Jon Lorsch, Ph.D., National Institute of General Medical Sciences
Nelson Mandela said, “Education is the most powerful weapon which you can use to change the world.” At NIH’s National Institute of General Medical Sciences (NIGMS), we believe that educating future and current scientists from diverse backgrounds benefits the entire biomedical research enterprise, changing the world through advances in disease diagnosis, treatment, and prevention.
As the summer winds down and students and educators embark on a new school year, I thought I’d highlight some of our educational resources that complement science, technology, engineering, and math (STEM) curricula. I’d also like to draw your attention to training programs designed to inspire and support research careers.
STEM Programs and Resources from NIH
The NIGMS Science Education Partnership Awards (SEPAs) are resources that provide opportunities for pre-K-12 students from underserved communities to access STEM educational resources. It lets them aspire to careers in health research.
The SEPA grants in almost every state support innovative, research-based, science education programs, furthering NIGMS’ mission to ensure a strong and diverse research ecosystem. Resources generated through SEPAs are free, mapped to state and national teaching standards for STEM, and rigorously evaluated for effectiveness. These resources include mobile laboratories, health exhibits in museums and science centers, educational resources for students, and professional development for teachers.
One SEPA program at Purdue University College of Veterinary Medicine, West Lafayette, IN, pairs veterinarians from their nationwide “superhero” League of VetaHumanz with local schools or community centers that support underserved students. These professional veterinarians, also from diverse backgrounds, strive to help young students from underrepresented groups envision future careers caring for animals.
Another SEPA program at Baylor University, Waco, TX, is increasing access to chemistry labs for high schoolers with blindness. It uses a robotic reactor with enhanced safety features to eliminate many dangers of synthetic organic chemistry. Students with blindness can control the robot to conduct experiments in a similar fashion to their sighted counterparts. The robot is housed within an airtight, blast-proof glove box, and it can perform common chemistry operations such as weighing and dispensing solid or liquid reagents; delivering solvents; combining reagents with the solvents; and stirring, heating, or cooling the reaction mixtures.
As noted in the 2021 report from the White House’s Office of Science and Technology Policy, “equity and inclusion are fundamental prerequisites for making high-quality STEM education accessible to all Americans and will maximize the creative capacity of tomorrow’s workforce.” I believe this statement falls right in line with the spirit of SEPAs.
New NIH-Wide STEM Teaching Resources Website
To help educators find free science education content, we recently launched a STEM teaching resources website. It includes NIH-wide teaching materials as well as those from SEPA programs for grades K-12, categorized by different health and research topic areas.
The NIGMS free educational resource Pathways, designed for educators and aspiring scientists in grades 6-12, is one of many resources available through the STEM website. Each issue of Pathways provides information about basic biomedical science and research careers and includes a student magazine, teacher lesson plans, and interactives such as Kahoot! classroom quizzes. Our most recent vaccine science issue teaches students how COVID-19 vaccines work in the body and introduces them to scientists dedicated to vaccine research.
Programs for Early Career Scientists
While SEPA grants focus on future scientists (and their educators) in grades pre-K-12, NIGMS also has a robust research training portfolio for those at the undergraduate through postdoctoral and professional levels. These programs aim to enhance diversity by engaging and training scientists from diverse backgrounds early in their careers.
At the undergraduate level, programs like Maximizing Access to Research Careers (MARC) provide students from diverse backgrounds with mentorship and career development. We recently highlighted the MARC program at Vanderbilt University, Nashville, TN, on our Biomedical Beat blog showing the program’s impact on students.
At the other end of the spectrum, our Maximizing Opportunities for Scientific and Academic Independent Careers (MOSAIC) program helps promising postdoctoral researchers from diverse backgrounds transition into independent faculty careers. The MOSAIC scholars become part of a career development program to expand their professional networks and gain additional skills and mentoring through scientific societies. You can learn more about each of these impressive early career scientists on our MOSAIC Scholars webpages.
At NIGMS, we’re dedicated to increasing the diversity of the biomedical research workforce. Through STEM content and outreach, as well as scientist training resources, we focus on emphasizing diversity, equity, inclusion, and accessibility. This holds true with funding and programming for current scientists, and in the inspiration and training of future scientists.
Links:
STEM Teaching Resources Website (NIH)
Science Education Partnership Award (SEPA) (NIH)
SEPA Award (National Institute of General Medical Sciences/NIH)
The League of VetaHumanz: Encouraging Kids to Use Their Powers for Good! (Biomedical Beat Blog/NIGMS)
Pathways (NIGMS)
Maximizing Access to Research Careers (MARC) Awards (NIGMS)
Catching Up With ReMARCable Vanderbilt Graduates (Biomedical Beat Blog/NIGMS)
Maximizing Opportunities for Scientific and Academic Independent Careers (MOSAIC) (NIGMS)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes and Centers (ICs) to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 15th in the series of NIH IC guest posts that will run until a new permanent NIH director is in place.
Artificial Intelligence Getting Smarter! Innovations from the Vision Field
Posted on by Michael F. Chiang, M.D., National Eye Institute
One of many health risks premature infants face is retinopathy of prematurity (ROP), a leading cause of childhood blindness worldwide. ROP causes abnormal blood vessel growth in the light-sensing eye tissue called the retina. Left untreated, ROP can lead to lead to scarring, retinal detachment, and blindness. It’s the disease that caused singer and songwriter Stevie Wonder to lose his vision.
Now, effective treatments are available—if the disease is diagnosed early and accurately. Advancements in neonatal care have led to the survival of extremely premature infants, who are at highest risk for severe ROP. Despite major advancements in diagnosis and treatment, tragically, about 600 infants in the U.S. still go blind each year from ROP. This disease is difficult to diagnose and manage, even for the most experienced ophthalmologists. And the challenges are much worse in remote corners of the world that have limited access to ophthalmic and neonatal care.
Artificial intelligence (AI) is helping bridge these gaps. Prior to my tenure as National Eye Institute (NEI) director, I helped develop a system called i-ROP Deep Learning (i-ROP DL), which automates the identification of ROP. In essence, we trained a computer to identify subtle abnormalities in retinal blood vessels from thousands of images of premature infant retinas. Strikingly, the i-ROP DL artificial intelligence system outperformed even international ROP experts [1]. This has enormous potential to improve the quality and delivery of eye care to premature infants worldwide.
Of course, the promise of medical artificial intelligence extends far beyond ROP. In 2018, the FDA approved the first autonomous AI-based diagnostic tool in any field of medicine [2]. Called IDx-DR, the system streamlines screening for diabetic retinopathy (DR), and its results require no interpretation by a doctor. DR occurs when blood vessels in the retina grow irregularly, bleed, and potentially cause blindness. About 34 million people in the U.S. have diabetes, and each is at risk for DR.
As with ROP, early diagnosis and intervention is crucial to preventing vision loss to DR. The American Diabetes Association recommends people with diabetes see an eye care provider annually to have their retinas examined for signs of DR. Yet fewer than 50 percent of Americans with diabetes receive these annual eye exams.
The IDx-DR system was conceived by Michael Abramoff, an ophthalmologist and AI expert at the University of Iowa, Iowa City. With NEI funding, Abramoff used deep learning to design a system for use in a primary-care medical setting. A technician with minimal ophthalmology training can use the IDx-DR system to scan a patient’s retinas and get results indicating whether a patient should be sent to an eye specialist for follow-up evaluation or to return for another scan in 12 months.
Many other methodological innovations in AI have occurred in ophthalmology. That’s because imaging is so crucial to disease diagnosis and clinical outcome data are so readily available. As a result, AI-based diagnostic systems are in development for many other eye diseases, including cataract, age-related macular degeneration (AMD), and glaucoma.
Rapid advances in AI are occurring in other medical fields, such as radiology, cardiology, and dermatology. But disease diagnosis is just one of many applications for AI. Neurobiologists are using AI to answer questions about retinal and brain circuitry, disease modeling, microsurgical devices, and drug discovery.
If it sounds too good to be true, it may be. There’s a lot of work that remains to be done. Significant challenges to AI utilization in science and medicine persist. For example, researchers from the University of Washington, Seattle, last year tested seven AI-based screening algorithms that were designed to detect DR. They found under real-world conditions that only one outperformed human screeners [3]. A key problem is these AI algorithms need to be trained with more diverse images and data, including a wider range of races, ethnicities, and populations—as well as different types of cameras.
How do we address these gaps in knowledge? We’ll need larger datasets, a collaborative culture of sharing data and software libraries, broader validation studies, and algorithms to address health inequities and to avoid bias. The NIH Common Fund’s Bridge to Artificial Intelligence (Bridge2AI) project and NIH’s Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity (AIM-AHEAD) Program project will be major steps toward addressing those gaps.
So, yes—AI is getting smarter. But harnessing its full power will rely on scientists and clinicians getting smarter, too.
References:
[1] Automated diagnosis of plus disease in retinopathy of prematurity using deep convolutional neural networks. Brown JM, Campbell JP, Beers A, Chang K, Ostmo S, Chan RVP, Dy J, Erdogmus D, Ioannidis S, Kalpathy-Cramer J, Chiang MF; Imaging and Informatics in Retinopathy of Prematurity (i-ROP) Research Consortium. JAMA Ophthalmol. 2018 Jul 1;136(7):803-810.
[2] FDA permits marketing of artificial intelligence-based device to detect certain diabetes-related eye problems. Food and Drug Administration. April 11, 2018.
[3] Multicenter, head-to-head, real-world validation study of seven automated artificial intelligence diabetic retinopathy screening systems. Lee AY, Yanagihara RT, Lee CS, Blazes M, Jung HC, Chee YE, Gencarella MD, Gee H, Maa AY, Cockerham GC, Lynch M, Boyko EJ. Diabetes Care. 2021 May;44(5):1168-1175.
Links:
Retinopathy of Prematurity (National Eye Institute/NIH)
Diabetic Eye Disease (NEI)
Michael Abramoff (University of Iowa, Iowa City)
Bridge to Artificial Intelligence (Common Fund/NIH)
[Note: Acting NIH Director Lawrence Tabak has asked the heads of NIH’s institutes and centers to contribute occasional guest posts to the blog as a way to highlight some of the cool science that they support and conduct. This is the second in the series of NIH institute and center guest posts that will run until a new permanent NIH director is in place.]
Preventing Glaucoma Vision Loss with ‘Big Data’
Posted on by Dr. Francis Collins
Each morning, more than 2 million Americans start their rise-and-shine routine by remembering to take their eye drops. The drops treat their open-angle glaucoma, the most-common form of the disease, caused by obstructed drainage of fluid where the eye’s cornea and iris meet. The slow drainage increases fluid pressure at the front of the eye. Meanwhile, at the back of the eye, fluid pushes on the optic nerve, causing its bundled fibers to fray and leading to gradual loss of side vision.
For many, the eye drops help to lower intraocular pressure and prevent vision loss. But for others, the drops aren’t sufficient and their intraocular pressure remains high. Such people will need next-level care, possibly including eye surgery, to reopen the clogged drainage ducts and slow this disease that disproportionately affects older adults and African Americans over age 40.
Credit: University of California San Diego
Sally Baxter, a physician-scientist with expertise in ophthalmology at the University of California, San Diego (UCSD), wants to learn how to predict who is at greatest risk for serious vision loss from open-angle and other forms of glaucoma. That way, they can receive more aggressive early care to protect their vision from this second-leading cause of blindness in the U.S..
To pursue this challenging research goal, Baxter has received a 2020 NIH Director’s Early Independence Award. Her research will build on the clinical observation that people with glaucoma frequently battle other chronic health problems, such as high blood pressure, diabetes, and heart disease. To learn more about how these and other chronic health conditions might influence glaucoma outcomes, Baxter has begun mining a rich source of data: electronic health records (EHRs).
In an earlier study of patients at UCSD, Baxter showed that EHR data helped to predict which people would need glaucoma surgery within the next six months [1]. The finding suggested that the EHR, especially information on a patient’s blood pressure and medications, could predict the risk for worsening glaucoma.
In her NIH-supported work, she’s already extended this earlier “Big Data” finding by analyzing data from more than 1,200 people with glaucoma who participate in NIH’s All of Us Research Program [2]. With consent from the participants, Baxter used their EHRs to train a computer to find telltale patterns within the data and then predict with 80 to 99 percent accuracy who would later require eye surgery.
The findings confirm that machine learning approaches and EHR data can indeed help in managing people with glaucoma. That’s true even when the EHR data don’t contain any information specific to a person’s eye health.
In fact, the work of Baxter and other groups have pointed to an especially important role for blood pressure in shaping glaucoma outcomes. Hoping to explore this lead further with the support of her Early Independence Award, Baxter also will enroll patients in a study to test whether blood-pressure monitoring smart watches can add important predictive information on glaucoma progression. By combining round-the-clock blood pressure data with EHR data, she hopes to predict glaucoma progression with even greater precision. She’s also exploring innovative ways to track whether people with glaucoma use their eye drops as prescribed, which is another important predictor of the risk of irreversible vision loss [3].
Glaucoma research continues to undergo great progress. This progress ranges from basic research to the development of new treatments and high-resolution imaging technologies to improve diagnostics. But Baxter’s quest to develop practical clinical tools hold great promise, too, and hopefully will help one day to protect the vision of millions of people with glaucoma around the world.
References:
[1] Machine learning-based predictive modeling of surgical intervention in glaucoma using systemic data from electronic health records. Baxter SL, Marks C, Kuo TT, Ohno-Machado L, Weinreb RN. Am J Ophthalmol. 2019 Dec; 208:30-40.
[2] Predictive analytics for glaucoma using data from the All of Us Research Program. Baxter SL, Saseendrakumar BR, Paul P, Kim J, Bonomi L, Kuo TT, Loperena R, Ratsimbazafy F, Boerwinkle E, Cicek M, Clark CR, Cohn E, Gebo K, Mayo K, Mockrin S, Schully SD, Ramirez A, Ohno-Machado L; All of Us Research Program Investigators. Am J Ophthalmol. 2021 Jul;227:74-86.
[3] Smart electronic eyedrop bottle for unobtrusive monitoring of glaucoma medication adherence. Aguilar-Rivera M, Erudaitius DT, Wu VM, Tantiongloc JC, Kang DY, Coleman TP, Baxter SL, Weinreb RN. Sensors (Basel). 2020 Apr 30;20(9):2570.
Links:
Glaucoma (National Eye Institute/NIH)
All of Us Research Program (NIH)
Video: Sally Baxter (All of Us Research Program)
Sally Baxter (University of California San Diego)
Baxter Project Information (NIH RePORTER)
NIH Director’s Early Independence Award (Common Fund)
NIH Support: Common Fund
The Amazing Brain: Making Up for Lost Vision
Posted on by Dr. Francis Collins
Recently, I’ve highlighted just a few of the many amazing advances coming out of the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative. And for our grand finale, I’d like to share a cool video that reveals how this revolutionary effort to map the human brain is opening up potential plans to help people with disabilities, such as vision loss, that were once unimaginable.
This video, produced by Jordi Chanovas and narrated by Stephen Macknik, State University of New York Downstate Health Sciences University, Brooklyn, outlines a new strategy aimed at restoring loss of central vision in people with age-related macular degeneration (AMD), a leading cause of vision loss among people age 50 and older. The researchers’ ultimate goal is to give such people the ability to see the faces of their loved ones or possibly even read again.
In the innovative approach you see here, neuroscientists aren’t even trying to repair the part of the eye destroyed by AMD: the light-sensitive retina. Instead, they are attempting to recreate the light-recording function of the retina within the brain itself.
How is that possible? Normally, the retina streams visual information continuously to the brain’s primary visual cortex, which receives the information and processes it into the vision that allows you to read these words. In folks with AMD-related vision loss, even though many cells in the center of the retina have stopped streaming, the primary visual cortex remains fully functional to receive and process visual information.
About five years ago, Macknik and his collaborator Susana Martinez-Conde, also at Downstate, wondered whether it might be possible to circumvent the eyes and stream an alternative source of visual information to the brain’s primary visual cortex, thereby restoring vision in people with AMD. They sketched out some possibilities and settled on an innovative system that they call OBServ.
Among the vital components of this experimental system are tiny, implantable neuro-prosthetic recording devices. Created in the Macknik and Martinez-Conde labs, this 1-centimeter device is powered by induction coils similar to those in the cochlear implants used to help people with profound hearing loss. The researchers propose to surgically implant two of these devices in the rear of the brain, where they will orchestrate the visual process.
For technical reasons, the restoration of central vision will likely be partial, with the window of vision spanning only about the size of one-third of an adult thumbnail held at arm’s length. But researchers think that would be enough central vision for people with AMD to regain some of their lost independence.
As demonstrated in this video from the BRAIN Initiative’s “Show Us Your Brain!” contest, here’s how researchers envision the system would ultimately work:
• A person with vision loss puts on a specially designed set of glasses. Each lens contains two cameras: one to record visual information in the person’s field of vision; the other to track that person’s eye movements enabled by residual peripheral vision.
• The eyeglass cameras wirelessly stream the visual information they have recorded to two neuro-prosthetic devices implanted in the rear of the brain.
• The neuro-prosthetic devices process and project this information onto a specific set of excitatory neurons in the brain’s hard-wired visual pathway. Researchers have previously used genetic engineering to turn these neurons into surrogate photoreceptor cells, which function much like those in the eye’s retina.
• The surrogate photoreceptor cells in the brain relay visual information to the primary visual cortex for processing.
• All the while, the neuro-prosthetic devices perform quality control of the visual signals, calibrating them to optimize their contrast and clarity.
While this might sound like the stuff of science-fiction (and this actual application still lies several years in the future), the OBServ project is now actually conceivable thanks to decades of advances in the fields of neuroscience, vision, bioengineering, and bioinformatics research. All this hard work has made the primary visual cortex, with its switchboard-like wiring system, among the brain’s best-understood regions.
OBServ also has implications that extend far beyond vision loss. This project provides hope that once other parts of the brain are fully mapped, it may be possible to design equally innovative systems to help make life easier for people with other disabilities and conditions.
Links:
Age-Related Macular Degeneration (National Eye Institute/NIH)
Macknik Lab (SUNY Downstate Health Sciences University, Brooklyn)
Martinez-Conde Laboratory (SUNY Downstate Health Sciences University)
Show Us Your Brain! (BRAIN Initiative/NIH)
Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative (NIH)
NIH Support: BRAIN Initiative
Regenerative Medicine: The Promise and Peril
Posted on by Dr. Francis Collins
Caption: Scanning electron micrograph of iPSC-derived retinal pigment epithelial cells growing on a nanofiber scaffold (blue).
Credit: Sheldon Miller, Arvydas Maminishkis, Robert Fariss, and Kapil Bharti, National Eye Institute/NIH
Stem cells derived from a person’s own body have the potential to replace tissue damaged by a wide array of diseases. Now, two reports published in the New England Journal of Medicine highlight the promise—and the peril—of this rapidly advancing area of regenerative medicine. Both groups took aim at the same disorder: age-related macular degeneration (AMD), a common, progressive form of vision loss. Unfortunately for several patients, the results couldn’t have been more different.
In the first case, researchers in Japan took cells from the skin of a female volunteer with AMD and used them to create induced pluripotent stem cells (iPSCs) in the lab. Those iPSCs were coaxed into differentiating into cells that closely resemble those found near the macula, a tiny area in the center of the eye’s retina that is damaged in AMD. The lab-grown tissue, made of retinal pigment epithelial cells, was then transplanted into one of the woman’s eyes. While there was hope that there might be actual visual improvement, the main goal of this first in human clinical research project was to assess safety. The patient’s vision remained stable in the treated eye, no adverse events occurred, and the transplanted cells remained viable for more than a year.
Exciting stuff, but, as the second report shows, it is imperative that all human tests of regenerative approaches be designed and carried out with the utmost care and scientific rigor. In that instance, three elderly women with AMD each paid $5,000 to a Florida clinic to be injected in both eyes with a slurry of cells, including stem cells isolated from their own abdominal fat. The sad result? All of the women suffered severe and irreversible vision loss that left them legally or, in one case, completely blind.
Snapshots of Life: Lighting up the Promise of Retinal Gene Therapy
Posted on by Dr. Francis Collins
Caption: Large-scale mosaic confocal micrograph showing expression of a marker gene (yellow) transferred by gene therapy techniques into the ganglion cells (blue) of a mouse retina.
Credit: Keunyoung Kim, Wonkyu Ju, and Mark Ellisman, National Center for Microscopy and Imaging Research, University of California, San Diego
The retina, like this one from a mouse that is flattened out and captured in a beautiful image, is a thin tissue that lines the back of the eye. Although only about the size of a postage stamp, the retina contains more than 100 distinct cell types that are organized into multiple information-processing layers. These layers work together to absorb light and translate it into electrical signals that stream via the optic nerve to the brain.
In people with inherited disorders in which the retina degenerates, an altered gene somewhere within this nexus of cells progressively robs them of their sight. This has led to a number of human clinical trials—with some encouraging progress being reported for at least one condition, Leber congenital amaurosis—that are transferring a normal version of the affected gene into retinal cells in hopes of restoring lost vision.
To better understand and improve this potential therapeutic strategy, researchers are gauging the efficiency of gene transfer into the retina via an imaging technique called large-scale mosaic confocal microscopy, which computationally assembles many small, high-resolution images in a way similar to Google Earth. In the example you see above, NIH-supported researchers Wonkyu Ju, Mark Ellisman, and their colleagues at the University of California, San Diego, engineered adeno-associated virus serotype 2 (AAV2) to deliver a dummy gene tagged with a fluorescent marker (yellow) into the ganglion cells (blue) of a mouse retina. Two months after AAV-mediated gene delivery, yellow had overlaid most of the blue, indicating the dummy gene had been selectively transferred into retinal ganglion cells at a high rate of efficiency [1].
Snapshots of Life: Seeing, from Eye to Brain
Posted on by Dr. Francis Collins
| Credit: Xueting Luo and Kevin Park, University of Miami |
Fasten your seat belts! We’re going to fly through the brain of a mouse. Our tour guide is Kevin Park, an NIH-funded neuroscientist at the University of Miami, who has developed a unique method to visualize neurons in an intact brain. He’s going to give us a rare close-up of the retinal ganglion cells that carry information from the eye to the brain, where the light signals are decoded and translated.
To make this movie, Park has injected a fluorescent dye into the mouse eye; it is taken up by the retinal cells and traces out the nerve pathways from the optic nerve into the brain.
Meet Alex—Before and After NIH Clinical Trial
Posted on by Dr. Francis Collins
Caption: Alex, then and now, with Dr. Goldbach-Mansky
Credit: Kate Barton and Susan Bettendorf (NIH)
Alex Barton recently turned 17. That’s incredible because Alex was born with a rare, often fatal genetic disease and wasn’t expected to reach his teenage years.
When Alex was born, he looked like he’d been dipped in boiling water: his skin was bright red and blistered. He spent most of his time sleeping. When awake, he screamed in agony from headaches, joint pain, and rashes. After a torturous 14 months, a rheumatologist told his mother that Alex suffered from Neonatal-Onset Multisystem Inflammatory Disease (NOMID). The doctor showed her a brief and scary paragraph in a medical text. Kate Barton, Alex’s mother, admitted that it “knocked her over like a freight train.”
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