Farsighted engineer invents bionic eye to help the blind

For UCLA bioengineering professor Wentai Liu, more than two decades of visionary research burst into the headlines last month when the FDA approved what it called “the first bionic eye for the blind.”

The Argus II Retinal Prosthesis System — developed by a team of physicians and engineers from around the country — aids adults who have lost their eyesight due to retinitis pigmentosa (RP), age-related macular degeneration or other eye diseases that destroy the retina’s light-sensitive photoreceptors.

At the heart of the device is a tiny yet powerful computer chip developed by Liu that, when implanted in the retina, effectively sidesteps the damaged photoreceptors to “trick” the eye into seeing. The Argus II operates with a miniature video camera mounted on a pair of eyeglasses that sends information about images it detects to a microprocessor worn on the user’s waistband. The microprocessor wirelessly transmits electronic signals to the computer chip, a fingernail-size grid made up of 60 circuits. These chips stimulate the retina’s nerve cells with electronic impulses which head up the optic nerve to the brain’s visual cortex. There, the brain assembles them into a composite image.

Recipients of the retinal implant can read oversized letters of the alphabet, discern objects and movement, and even see the outlines and some details of faces. And while the picture is far from perfect — the healthy human eye sees at a much higher resolution — it’s a breakthrough for people like the first patient, a man in his 70s who was blinded at age 20 by RP, to receive the implant in clinical trials. “It was the first time he’d seen light in a half-century,” said Liu, adding that “it feels good as the engineer” to have helped make this possible.

Liu joined the Artificial Retina Project in 1988 as a professor of computer and electrical engineering at North Carolina State University. The multidisciplinary research project was funded by the U.S. Department of Energy’s Office of Science because it envisioned a potential pandemic of eyesight loss in America’s aging population. Leading the project was Duke University ophthalmologist and neurosurgeon Dr. Mark Humayun, now on faculty at USC. He tapped Liu to engineer the artificial retina.

“I thought it was a great idea,” Liu said. “But I asked, ‘What can I do?’ because I didn’t know much about biology.” Humayun handed him a six-inch-thick medical manual on the retina. “The learning curve was very steep,” Liu recalled with a laugh.

However, Liu’s fellow engineers questioned his sanity. “I was working on integrated chip design and had just gotten tenure when I signed on to this project. They said, ‘You’re crazy!’ But I’m glad I made that choice, getting into this new field.”

How the bionic eye works

Cell death in retina helps tune our internal clocks

With every sunrise and sunset, our eyes make note of the light as it waxes and wanes, a process that is critical to aligning our circadian rhythms to match the solar day so we are alert during the day and restful at night. Watching the sun come and go sounds like a peaceful process, but Johns Hopkins scientists have discovered that behind the scenes, millions of specialized cells in our eyes are fighting for their lives to help the retina set the stage to keep our internal clocks ticking.

In a study that appeared in a recent issue of Neuron, a team led by biologist Samer Hattar has found that there is a kind of turf war going on behind our eyeballs, where intrinsically photosensitive retinal ganglion cells (ipRGCs) are jockeying for the best position to receive information from rod and cone cells about light levels. By studying these specialized cells in mice, Hattar and his team found that the cells actually kill each other to seize more space and find the best position to do their job.

Understanding this fight could one day lead to victories against several conditions, including autism and some psychiatric disorders, where neural circuits influence our behavior. The results could help scientists have a better idea about how the circuits behind our eyes assemble to influence our physiological functions, said Hattar, an associate professor of biology in the Krieger School of Arts and Sciences.

“In a nutshell, death in our retina plays a vital role in assembling the retinal circuits that influence crucial physiological functions such as circadian rhythms and sleep-wake cycles,” Hattar said. “Once we have a greater understanding of the circuit formation underlying all of our neuronal abilities, this could be applied to any neurological function.”

Hattar and his team determined that the killing among rival ipRGCs is justifiable homicide: Without this cell death, circadian blindness overcame the mice, who could no longer distinguish day from night. Hattar’s team studied mice that were genetically modified to prevent cell death by removing the Bax protein, an essential factor for cell death to occur. They discovered that if cell death is prevented, ipRGCs distribution is highly affected, leading the surplus cells to bunch up and form ineffectual, ugly clumps incapable of receiving light information from rods and cones for the alignment of circadian rhythms. To detect this, the researchers used wheel running activity measurements in mice that lacked the Bax protein as well as the melanopsin protein which allows ipRGCs to respond only through rods and cones and compared it to animals where only the Bax gene was deleted.

What the authors uncovered was exciting: When death is prevented, the ability of rods and cones to signal light to our internal clocks is highly impaired. This shows that cell death plays an essential role in setting the circuitry that allows the retinal rods and cones to influence our circadian rhythms and sleep.

(Image: Advanced Retinal Institute, Inc.)

Holographic Technique Could Lead to Bionic Vision

Researchers led by biomedical engineering Professor Shy Shoham of the Technion-Israel Institute of Technology are testing the power of holography to artificially stimulate cells in the eye, with hopes of developing a new strategy for bionic vision restoration.

Computer-generated holography, they say, could be used in conjunction with a technique called optogenetics, which uses gene therapy to deliver light-sensitive proteins to damaged retinal nerve cells. In conditions such as Retinitis Pigmentosa (RP) - a condition affecting about one in 4000 people in the United States - these light-sensing cells degenerate and lead to blindness.

“The basic idea of optogenetics is to take a light-sensitive protein from another organism, typically from algae or bacteria, and insert it into a target cell, and that photosensitizes the cell,” Shoham explained.

Intense pulses of light can activate nerve cells newly sensitized by this gene therapy approach. But Shoham said researchers around the world are still searching for the best way to deliver the light patterns so that the retina “sees” or responds in a nearly normal way.

The plan is to someday develop a prosthetic headset or eyepiece that a person could wear to translate visual scenes into patterns of light that stimulate the genetically altered cells.

In their paper in the February 26 issue of Nature Communications, the Technion researchers show how light from computer-generated holography could be used to stimulate these repaired cells in mouse retinas. The key, they say, is to use a light stimulus that is intense, precise, and can trigger activity across a variety of cells all at once.

Retinal implant wins FDA approval

The U.S. Food and Drug Administration (FDA) approved the Argus II retinal prosthesis system for use in the United States.

Mark Humayun, who holds joint appointments at the Keck School of Medicine of USC and the USC Viterbi School of Engineering, was a key member of the team that developed the device, which will be available to qualified patients at the Keck Medical Center of USC.

The Argus II, which received a unanimous recommendation for approval by the FDA’s Ophthalmic Devices Advisory Panel in September, restores some visual capabilities for patients whose blindness is caused by Retinitis Pigmentosa (RP), an inherited retinal degenerative disease that affects about 100,000 people nationwide.

“It is incredibly exciting to have FDA approval to begin implanting the Argus II and provide some restoration of vision to patients blinded from RP,” said Humayun, Cornelius Pings Professor of Biomedical Sciences and professor of ophthalmology, biomedical engineering, cell and neurobiology at USC. “In the patients that have been implanted to date, the improvement in the quality of life has been invaluable.

“The fact that many patients can use the Argus implant in their activities of daily living, such as recognizing large letters, locating the position of objects and more, has been beyond our wildest dreams,” Humayun added, “yet the promise to the patients is real, and we expect it only to improve over time.”

The Argus II, which is manufactured by Sylmar, Calif.-based Second Sight, was approved for use in Europe in 2011 and has been implanted in 30 patients in a clinical trial that began in 2007. Humayun performed many of the surgeries to implant the device.

The FDA approval paves the way for Second Sight to build a surgical network in the United States to implant the device, as well as to recruit hospitals to offer it, according to Robert Greensburg, president and CEO of the company.

The Argus II system uses a camera mounted on special glasses that sends a signal to an electronic receiver with 60 electrodes implanted inside the eye.

The receiver sends signals to the retina that travel through the optic nerve to the brain, where they can be interpreted as a visual picture. The researchers hope that one day the device can be improved to also help individuals with age-related macular degeneration, a similar but far more common disease.

Public inquiries regarding the Argus II can be directed to the Second Sight public information line at (855) 756-3703.

As the Argus II retinal implant is refined, it will be housed in the USC Institute of Biomedical Therapeutics. The new $60 million endowed interdisciplinary institute will bring together scientists, engineers and clinicians from around the world to study neural networks to develop bioelectronic solutions for the millions of people impacted by traumatic brain injury, stroke and debilitating eye diseases.

Research finds protein that prevents light-induced retinal degeneration

Research led by Minghao Jin, PhD, Assistant Professor of Ophthalmology and Neuroscience at the LSU Health Sciences Center New Orleans Neuroscience Center of Excellence, has found a protein that protects retinal photoreceptor cells from degeneration caused by light damage. This protein may provide a new therapeutic target for both an inherited retinal degenerative disease and age-related macular degeneration. The paper is published in the February 13, 2013 issue of the Journal of Neuroscience.

The visual cycle is essential for regenerating visual pigments that sense light for vision. However, abnormal visual cycles promote formation of toxic byproducts that contribute to the development of age-related macular degeneration (AMD), the leading cause of vision loss in elderly people that affects an estimated 2 million Americans. The mechanisms that regulate the visual cycle have been unclear. Identification and characterization of regulators of the visual cycle enzymes are critical for understanding these mechanisms.

RPE65 is a key enzyme involved in the visual cycle. RPE65 mutations have been linked to early onset vision loss, retinal degeneration, and blinding eye diseases. Despite such importance, the mechanisms that regulate the function of RPE65 are unknown. To identify and characterize previously unknown inhibitors of RPE65, the scientists tested five candidate proteins. Using gene screening, the LSUHSC research team discovered that one of them – fatty acid transport protein 4 (FATP4) – is a negative regulator; it inhibits RPE65.

"We found that FATP4 protects retinal photoreceptor cells from experimentally-induced retinal degeneration," notes Nicolas Bazan, MD, PhD, Boyd Professor, Ernest C. and Yvette C. Villere Endowed Chair of Retinal Degeneration, and Director of the LSU Health Sciences Center New Orleans Neuroscience Center of Excellence, who is a co-author of the paper.

Recently, mutations in the human FATP4 gene have been identified in patients with a certain recessive disorder which also features one of the toxic byproducts associated with abnormal visual cycles. This byproduct, called A2E accumulates in retinal pigment epithelial cells with age, prompting a call for further investigation to determine whether FATP4 mutations cause age-related vision impairment and retinal degeneration.

"These findings suggest that FATP4 may be a therapeutic target for the inherited retinal degenerative disease caused by RPE65 mutations and AMD," concludes Dr. Jin.

(Image: Eyeland Design Network)

Altering eye cells may one day restore vision

Doctors may one day treat some forms of blindness by altering the genetic program of the light-sensing cells of the eye, according to scientists at Washington University School of Medicine in St. Louis.

Working in mice with retinitis pigmentosa, a disease that causes gradual blindness, the researchers reprogrammed the cells in the eye that enable night vision. The change made the cells more similar to other cells that provide sight during daylight hours and prevented degeneration of the retina, the light-sensing structure in the back of the eye. The scientists now are conducting additional tests to confirm that the mice can still see.

“We think it may be significantly easier to preserve vision by modifying existing cells in the eye than it would be to introduce new stem cells,” says senior author Joseph Corbo, MD, PhD, assistant professor of pathology and immunology. “A diseased retina is not a hospitable environment for transplanting stem cells.”

The study is available in the early online edition of Proceedings of the National Academy of Sciences.

Mutations in more than 200 genes have been linked to various forms of blindness. Efforts are underway to develop gene therapies for some of these conditions.

Rather than seek treatments tailored to individual mutations, Corbo hopes to develop therapies that can alleviate many forms of visual impairment. To make that possible, he studies the genetic factors that allow cells in the developing eye to take on the specialized roles necessary for vision.

Study Sheds Light on the Complexity of Gene Therapy for Congenital Blindness

Independent clinical trials, including one conducted at the Scheie Eye Institute at the Perelman School of Medicine, have reported safety and efficacy for Leber congenital amaurosis (LCA), a congenital form of blindness caused by mutations in a gene (RPE65) required for recycling vitamin A in the retina. Inherited retinal degenerative diseases were previously considered untreatable and incurable. There were early improvements in vision observed in the trials, but a key question about the long-term efficacy of gene therapy for curing the retinal degeneration in LCA has remained unanswered. Now, new research from the Scheie Eye Institute, published this week in the Proceedings of the National Academy of Sciences, finds that gene therapy for LCA shows enduring improvement in vision but also advancing degeneration of affected retinal cells, both in LCA patients and animal models of the same condition.

LCA disease from RPE65 mutations has two-components: a biochemical blockade leading to impaired vision, and a progressive loss of the light-sensing photoreceptor cells throughout life of the affected patient. The authors of the new study explain that until now gene therapy has been optimistically assumed, but not proven, to solve both disease components at the same time.

“We all hoped that the gene injections cured both components – re-establishing the cycle of vision and also preventing further loss of cells to the second disease component” said Artur V. Cideciyan, PhD, lead author and co-investigator of an LCA clinical trial at Penn.

Yet, when the otherwise invisible cell layers of the retina were measured by optical imaging in clinical trial participants serially over many years, the rate of cell loss was the same in treated and untreated regions. “In other words, gene therapy improved vision but did not slow or halt the progression of cell loss,” commented Cideciyan.

“These unexpected observations should help to advance the current treatment by making it better and longer lasting,” commented co-author Samuel G. Jacobson, MD, PhD, principal investigator of the clinical trial. “Slowing cell loss in different retinal degenerations has been a major research direction long before the current gene therapy trials. Now, the two directions must converge to ensure the longevity of the beneficial visual effects in this form of LCA.”

(Image: bigstockphoto)

Light Exposure During Pregnancy Key to Normal Eye Development

New research in Nature concludes the eye – which depends on light to see – also needs light to develop normally during pregnancy.

Scientists say the unexpected finding offers a new basic understanding of fetal eye development and ocular diseases caused by vascular disorders – in particular one called retinopathy of prematurity that can blind premature infants. The research, led by scientists at Cincinnati Children’s Hospital Medical Center and the University of California, San Francisco (UCSF), appears online Jan. 16 ahead of print publication.

“This fundamentally changes our understanding of how the retina develops,” says study co-author Richard Lang, PhD, a researcher in the Division of Pediatric Ophthalmology at Cincinnati Children’s Hospital Medical Center. “We have identified a light-response pathway that controls the number of retinal neurons. This has downstream effects on developing vasculature in the eye and is important because several major eye diseases are vascular diseases.”

Lang is a principal investigator on the ongoing research along with project collaborator, David Copenhagen, PhD, a scientist in the departments of Ophthalmology and Physiology at UCSF. The scientists say their current study, conducted in mouse models, includes several unexpected findings.

"Several stages of mouse eye development occur after birth," says Copenhagen. "Because of this, we had always assumed that if light played a role in the development of the eye, it would also happen only after birth."

But researchers in the current study found that activation of the newly described light-response pathway must happen during pregnancy to activate the carefully choreographed program that produces a healthy eye. Specifically, they say it is important for a sufficient number of photons to enter the mother’s body by late gestation, or about 16 days into a mouse pregnancy.

Researchers were also surprised to learn that photons of light activate a protein called melanopsin directly in the fetus – not the mother – to help initiate normal development of blood vessels and retinal neurons in the eye.

One purpose of the light-response pathway is to suppress the number of blood vessels that form in the retina. These vessels are critical to retinal neurons, which require large amounts of oxygen to form and to function. When retinopathy of prematurity occurs in infants, retinal vessels grow almost unchecked. This continued expansion puts intense pressure on the developing eye and in extreme cases causes severe damage and blindness.

The research team led by Lang and Copenhagen conducted several experiments in laboratory mouse models that allowed them to identify the light-response pathway’s specific components and function.

Mice were reared in the dark and in a normal day-night cycle beginning at late gestation to observe the comparative effects on vascular development of the eye. The researchers verified the function of the light response pathway by mutating an opsin gene in mice called Opn4 that produces melanopsin, in essence preventing activation of the photo pigment.

Both mice reared under dark conditions from late gestation, and those with mutated Opn4, exhibited nearly identical promiscuous expansion of hyaloid vessels and abnormal retinal vascular growth. The unchecked vascular growth was driven by the protein vascular endothelial growth factor (Vegfa). When the light response pathway is properly engaged, it modulates Vegfa to help prevent promiscuous vascular growth, according to researchers.

The melanopsin protein is present in both mice and humans during pregnancy. Lang said the research team is continuing to study how the light-response pathway might influence the susceptibility of pre-term infants to retinopathy of prematurity and also be related to other diseases of the eye.

Specific protein essential for healthy eyes

Researchers at the Hebrew University of Jerusalem, in collaboration with researchers at the Salk Institute in California,  have found for the first time that a specific protein is essential not only for maintaining a healthy retina in the eye, but also may have implications for understanding and possibly treating other conditions in the immune, reproductive, vascular and nervous systems, as well as in various cancers.

Their work, reported online in the journal Neuron, highlights the role of Protein S in the maintenance of a healthy retina through its involvement in the process of pruning photoreceptors, the light-sensitive neurons in the eye. (This process is also referred to as phagocytosis.) These photoreceptors keep growing and elongating from their inner end. In order to maintain a constant length, they must be pruned from their outer end by specialized cells called retinal pigment epithelial cells.

Without such pruning — which also clears away many free radicals and toxic by-products generated during visual biochemical reactions — photoreceptors would succumb to toxicity and degenerate, leading if unchecked to blindness. A receptor molecule called Mer is a key in photoreceptor pruning, and is therefore vital for retinal health. Mutations in the mouse, rat and human Mer genes cause retinal degeneration, which finally leads to blindness.

The Hebrew University study published in Neuron focuses on the molecules activating Mer in this pruning mechanism. Although two such molecules – Gas6 and Protein S — were identified previously, it was yet to be proven that they also play a role in a living organism. To show this, Dr. Tal Burstyn-Cohen of the Hebrew University Institute of Dental Sciences and colleagues at the Salk Institute in California found in their experiments on laboratory animals that both Gas6 and Protein S are needed to activate phagocytosis, or pruning, of retinal photoreceptors, and thus keep a healthy retina.

These findings could have practical implications, since Protein S also functions as a potent blood anticoagulant. People with Protein S deficiency are at risk for life threatening thrombosis (blood clots) and thromboembolism (a clot that breaks loose and is carried by the blood stream to plug another vessel).

These results further open new avenues of research into the role of Protein S in activating the receptors in other tissues where their function was shown to be important, such as in the immune, reproductive, vascular and nervous systems, as well as in various cancers where activation of receptors has been observed. For example, since Protein S is important for blood vessel formation, neutralizing Protein S in the blood vessels supplying blood to cancer growths could interfere with the cancerous blood supply.

(Image: Gemma Bou/Getty Images)