Bionic eye maker has vision of the future

Robert Greenberg got tired of hearing from senior engineers that it wasn’t possible to build his product idea: a bionic eye that gives sight to the blind.

"A lot of the folks straight out of school didn’t know any better, so I hired them instead," quipped Greenberg, chief executive of Second Sight Medical Products Inc., a Sylmar biotech company. "They didn’t know how hard it was going to be, that it was impossible. And so they tried."

Greenberg can laugh now that he once thought developing the device would take a year and $1 million. Some 20 years and $200 million later, the first bionic eye has helped more than 20 European patients regain some of their sight.

Called the Argus II Retinal Prosthesis System, the device recently was approved by the Food and Drug Administration. Second Sight, which has 100 employees, is allowed to sell the bionic eye system to patients in the U.S. with advanced retinitis pigmentosa, a degenerative eye disease that can cause blindness.

"We are a far cry from restoring 20/20 vision," said Brian V. Mech, Second Sight’s vice president of business development, who holds a doctorate in materials science and an MBA from the UCLA Anderson School of Management.

"We are taking blind people back up to low vision, and that is pretty significant."

Mech likes to show videos of once-sightless patients who, after receiving the retinal prosthesis, are able to follow a person walking down the street and discern a street curb without using their canes.

"Until our product, these patients had no other option to obtain the ability to see," Mech said of the $100,000 device, part of which rests on a pair of Oakley Inc. sunglass frames. The cost to European patients has been paid by insurance companies in most cases.

Palo Alto attorney Dean Lloyd, who lost his vision 17 years ago, got the bionic eye system as part of the U.S. testing process. It allows him to see “boundaries and borders, not images” but has had a profound effect on his life.

Lloyd cites an incident before he received the eye system that still rankles. In the middle of a courtroom trial, an opposing attorney said Lloyd didn’t stand a chance with his case because he couldn’t even keep his socks straight: Lloyd had mixed up his black, courtroom socks with his white athletic ones.

"What did I do after the surgical procedure that I hadn’t been able to do?" Lloyd said. "I went home and sorted all of my socks."

The story of how the bionic eye came to be made in Sylmar underscores the state’s long record of medical device advances and involves top university researchers who were brought to Southern California to work on the project.

Greenberg likened the degree of difficulty to “shrinking a television set to the size of a pea, then throwing it into the ocean and expecting it to work.”

For Greenberg, it began in the early 1990s when he was a doctoral candidate in the Department of Biomedical Engineering at Johns Hopkins University in Baltimore.

Some of the first work was being done there, testing patients who had lost their vision because of retinitis pigmentosa, to see if electrically stimulating their retinas would produce results. It did.

"Using one electrode, the patient saw one spot of light," Greenberg said. "Second electrode, and the patient was seeing two spots of light. During that experiment, I was hooked."

Greenberg said he thought: “This is just engineering. Put more spots and you could make more pixels, like lights on a scoreboard or pixels on your computer monitor. You could see images.”

There was a breakthrough of another sort a few years later, in Washington. There, Greenberg was working as a medical officer and a lead reviewer for the FDA’s Office of Device Evaluation when he met entrepreneur Alfred E. Mann.

Mann had already established himself as a medical device developer through Mannkind Corp. and several other Southern California companies. During the 1980s, the self-made billionaire founded Pacesetter Systems, which made cardiac pacemakers. From there, he moved on to insulin pumps and related equipment.

Another Mann-funded company, Advanced Bionics Corp., took on cochlear implants, which could restore hearing to the deaf. It was the electrode-based cochlear implant that formed the rough basis of Second Sight’s first bionic eye.

In 1998, Second Sight opened with the financial backing of Mann and Sam Williams, another successful entrepreneur whose company, Williams International, designed and built small, efficient turbofan jet engines.

"Sam Williams was blind from retinitis pigmentosa, the disease that we are treating," Mech said. "He had invested along with Al in Advanced Bionics, which restores hearing for deaf people, and they were already on the market in the ’90s. Sam said to Al, ‘Why can’t we do the same for blind people?’"

Research Suggests Link Between Elevated Blood Sugar, Alzheimer’s Risk

A new University of Arizona study, published in the journal Neurology, suggests a possible link between elevated blood sugar levels and risk for developing Alzheimer’s disease.

About 5 percent of men and women, ages 65 to 74, have Alzheimer’s disease, and it is estimated that nearly half of those age 85 and older may have the disease, according to the U.S. Centers for Disease Control and Prevention. Among the known factors that contribute to the disease are age and genetics. Scientists also think that high blood pressure, high cholesterol and diabetes may increase risk.

Although the link between diabetes and Alzheimer’s has been studied, UA researchers wondered if elevated blood sugar levels in non-diabetic individuals also might indicate a higher risk for developing Alzheimer’s disease.

"There have been studies that have linked diabetes to Alzheimer’s disease as a risk factor," said Alfred Kaszniak, UA professor of psychology and a co-author on the study. "What was not known when we began this work is whether that risk was only at levels of blood sugar that qualify for diagnoses of diabetes, or in the borderline or pre-diabetic range, or would we also see a relationship across the so-called normal range of blood glucose?"

The researchers used fluorodeoxyglucose (18F) positron electron tomography, or FDG PET, a medical imaging technique that produces three-dimensional images of metabolic activity in the brain. Fasting serum glucose levels – blood sugar levels following several hours of not eating – are routinely acquired as part of the FDG PET protocol.

"When compared to those without the disease, Alzheimer’s disease patients demonstrate a pattern of reduced brain metabolism in particular brain regions," explained Christine Burns, lead author on the study and a UA pre-doctoral student in psychology. "What we show is an association between elevated fasting serum glucose levels and a similar pattern of reduced metabolism in these same AD-related brain regions in cognitively healthy adults."

The researchers studied data on 124 cognitively normal, non-diabetic adults with a family history of Alzheimer’s disease. The individuals, who ranged in age from 47 to 68, were among participants in a larger study, led by Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix, looking at a variety of Alzheimer’s risk factors, including genetic risk. 

The link between high blood sugar and reduced brain metabolism existed regardless of whether individuals carried the Apolipoprotein E4 gene variant, an established risk factor for the development of Alzheimer’s disease.   

In addition to suggesting a link between elevated blood sugar levels and Alzheimer’s risk in non-diabetic individuals, the study also shows promise for the use of brain imaging techniques like PET in identifying Alzheimer’s risk and developing early preventative interventions, researchers say.

"Right now, if you want to develop a drug or evaluate some other kind of a preventive measure for Alzheimer’s disease, the labor and expense is prohibitive," Kaszniak said. "If you recruit people who may be at some risk, but are 20 years away from developing signs of the illness, what drug company or governmental agency is going to fund research that follows people for 20 years to see whether something is effective in prevention?

"However, if you have a biologic marker, it suggests what areas you should really focus on in those very expensive longitudinal studies," he said.

Burns said she hopes the findings will inform ongoing work designed to help develop early Alzheimer’s interventions.

"A lot of valuable research is focused on treatment and slowing decline in Alzheimer’s patients," she said. "I’m interested in complementing this work with interventions that can be implemented earlier on, perhaps at middle age."

Commands from the matrix: Cellular environment controls formation and activity of neuronal connections

Environment moulds behaviour - and not just that of people in society, but also at the microscopic level. This is because, for their function, neurons are dependent on the cell environment, the so-termed extracellular matrix. Researchers at the Ruhr-Universität have found evidence that this complex network of molecules controls the formation and activity of the neuronal connections. The team led by Dr. Maren Geißler und Prof. Andreas Faissner from the Department of Cell Morphology and Molecular Neurobiology reports in the “Journal of Neuroscience” in collaboration with the team of Dr. Ainhara Aguado, Prof. Christian Wetzel and Prof. Hanns Hatt from the Department of Cell Physiology.

Neurons and astrocytes in culture

In cooperation with Prof. Uwe Rauch from Lund University in Sweden, Bochum’s biologists examined cells from the brains of two mouse species: a species with a normal extracellular matrix and a species which lacked four components of the extracellular matrix due to genetic manipulation, namely the molecules tenascin-C, tenascin-R, neurocan and brevican. They took the cells from the hippocampus, a brain structure that is crucial for the long-term memory. The team not only examined neurons but also astrocytes, which are in close contact with the neurons, support their function and secrete molecules for the extracellular matrix.

Formation, stability and activity of the neuronal connections depend on the matrix

The researchers cultivated the neurons and astrocytes together for four weeks with a specially developed culture strategy. Among other things, they observed how many connections, known as synapses, the neurons formed with each other and how stable these were over time. If either the astrocytes or the neurons in the culture dish derived from animals with a reduced extracellular matrix, these synapses proved to be less stable in the medium term, and their number was significantly reduced. Together with the Department of Cell Physiology at the RUB and the University of Regensburg, the team also showed that the neurons with a mutated matrix showed lower spontaneous activity than normal cells. The extracellular matrix thus regulates the formation, stability and activity of the neuronal connections. The researchers also examined a special structure of the extracellular matrix, the so-called perineuronal nets, which the Nobel laureate Camillo Golgi first described more than a century ago. They were significantly reduced in the environment of genetically modified cells.

Boosting ‘cellular garbage disposal’ can delay the aging process

UCLA life scientists have identified a gene previously implicated in Parkinson’s disease that can delay the onset of aging and extend the healthy life span of fruit flies. The research, they say, could have important implications for aging and disease in humans.

The gene, called parkin, serves at least two vital functions: It marks damaged proteins so that cells can discard them before they become toxic, and it is believed to play a key role in the removal of damaged mitochondria from cells.

"Aging is a major risk factor for the development and progression of many neurodegenerative diseases," said David Walker, an associate professor of integrative biology and physiology at UCLA and senior author of the research. "We think that our findings shed light on the molecular mechanisms that connect these processes."

In the research, published today in the early online edition of the journal Proceedings of the National Academy of Sciences, Walker and his colleagues show that parkin can modulate the aging process in fruit flies, which typically live less than two months. The researchers increased parkin levels in the cells of the flies and found that this extended their life span by more than 25 percent, compared with a control group that did not receive additional parkin.

"In the control group, the flies are all dead by Day 50," Walker said. "In the group with parkin overexpressed, almost half of the population is still alive after 50 days. We have manipulated only one of their roughly 15,000 genes, and yet the consequences for the organism are profound."

"Just by increasing the levels of parkin, they live substantially longer while remaining healthy, active and fertile," said Anil Rana, a postdoctoral scholar in Walker’s laboratory and lead author of the research. "That is what we want to achieve in aging research — not only to increase their life span but to increase their health span as well."

Treatments to increase parkin expression may delay the onset and progression of Parkinson’s disease and other age-related diseases, the biologists believe. (If parkin sounds related to Parkinson’s, it is. While the vast majority of people with the disease get it in older age, some who are born with a mutation in the parkin gene develop early-onset, Parkinson’s-like symptoms.)

"Our research may be telling us that parkin could be an important therapeutic target for neurodegenerative diseases and perhaps other diseases of aging," Walker said. "Instead of studying the diseases of aging one by one — Parkinson’s disease, Alzheimer’s disease, cancer, stroke, cardiovascular disease, diabetes — we believe it may be possible to intervene in the aging process and delay the onset of many of these diseases. We are not there yet, and it can, of course, take many years, but that is our goal."

'The garbage men in our cells go on strike'

To function properly, proteins must fold correctly, and they fold in complex ways. As we age, our cells accumulate damaged or misfolded proteins. When proteins fold incorrectly, the cellular machinery can sometimes repair them. When it cannot, parkin enables cells to discard the damaged proteins, said Walker, a member of UCLA’s Molecular Biology Institute.

"If a protein is damaged beyond repair, the cell can recognize that and eliminate the protein before it becomes toxic," he said. "Think of it like a cellular garbage disposal. Parkin helps to mark damaged proteins for disposal. It’s like parkin places a sticker on the damaged protein that says ‘Degrade Me,’ and then the cell gets rid of this protein. That process seems to decline with age. As we get older, the garbage men in our cells go on strike. Overexpressed parkin seems to tell them to get back to work."

Rana focused on the effects of increased parkin activity at the cellular and tissue levels. Do flies with increased parkin show fewer damaged proteins at an advanced age? “The remarkable finding is yes, indeed,” Walker said.

Parkin has recently been shown to perform a similarly important function with regard to mitochondria, the tiny power generators in cells that control cell growth and tell cells when to live and die. Mitochandria become less efficient and less active as we age, and the loss of mitochondrial activity has been implicated in Alzheimer’s, Parkinson’s and other neurodegenerative diseases, as well as in the aging process, Walker said.

Parkin appears to degrade the damaged mitochondria, perhaps by marking or changing their outer membrane structure, in effect telling the cell, “This is damaged and potentially toxic. Get rid of it.”

If parkin is good, is more parkin even better?

While the researchers found that increased parkin can extend the life of fruit flies, Rana also discovered that too much parkin can have the opposite effect — it becomes toxic to the flies. When he quadrupled the normal amount of parkin, the fruit flies lived substantially longer, but when he increased the amount by a factor of 30, the flies died sooner.

"If you bombard the cell with too much parkin, it could start eliminating healthy proteins," Rana said.

In the lower doses, however, the scientists found no adverse effects. Walker believes the fruit fly is a good model for studying aging in humans — who also have the parkin gene — because scientists know all of the fruit fly’s genes and can switch individual genes on and off.

Previous research has shown that fruit flies die sooner when you remove parkin, Walker noted.

Walker and Rana do not know what the optimal amount of parkin would be in humans.

While the biologists increased parkin activity in every cell in the fruit fly, Rana also conducted an experiment in which he increased parkin expression only in the nervous system. That, too, was sufficient to make the flies live longer.

"This tells us that parkin is neuroprotective during aging," Walker said. "However, the beneficial effects of parkin are greater — twice as large — when we increased its expression everywhere."

"We were excited about this research from the beginning but did not know then that the life span increase would be this impressive," Rana said.

The image that accompanies this news release shows clumps or aggregates of damaged proteins in an aged brain from a normal fly (left panel) and an age-matched brain with increased neuronal parkin levels (right panel). As can be seen, increasing parkin levels in the aging brain reduces the accumulation of aggregated proteins.

Scientists have found that this kind of protein aggregation occurs in mammals as well, including humans, Rana said.

"Imagine the damage the accumulation of protein trash is doing to the cell," Walker said. "With increased Parkin, the trash has been collected. Without it, the garbage that should be discarded is accumulating in the cells."

A tangle of talents untangles neurons

Brown’s growing programs in brain science and engineering come together in the lab of Diane Hoffman-Kim. In a recent paper, her group employed techniques ranging from semiconductor-style circuit patterning to rat cell culture to optimize the growth of nerve cells for applications such as reconstructive surgery.

Two wrongs don’t make a right, they say, but here’s how one tangle can straighten out another.

Diane Hoffman-Kim, associate professor of medicine in the Department of Molecular Pharmacology, Physiology, and Biotechnology, is an affiliate of both Brown’s Center for Biomedical Engineering and the Brown Institute for Brain Science. Every thread of expertise woven through those multidisciplinary titles mattered in the Hoffman-Kim lab’s most recent paper, led by graduate student Cristina Lopez-Fagundo.

In research published online last month in Acta Biomaterialia, Hoffman-Kim and Lopez-Fagundo employed their neurophysiological knowledge and technological ingenuity to unravel a tangle of branching, tendrilous nerve cells, or neurons.

The scientist-engineers helped explain how neurons grow in new tissues in response to physical guideposts, called Schwann cells. Their paper also provided medical device makers with an overt demonstration of how to craft the best artificial Schwann cell implants in silicone to make neurons grow as straight as possible in a desired direction.

“If you’ve got an injury in your arm or your leg then you’d like to have proper reconnection so you can get function,” Hoffman-Kim said. “If it’s a small injury, your body does that fairly well in natural ways that largely depend on the Schwann cells. If the injury gets even just a little bit large then the Schwann cells can’t do it alone.”

Silicone Schwanns

Hoffman-Kim and Lopez-Fagundo did not invent the idea of creating an implant to direct neural growth through repaired or reattached tissues. Their clinical goal is to make that technology the best it can be by systematically studying neural growth on Schwann-like substrates. As a matter of basic science, they wanted to learn how neural growth proceeds.

Lopez-Fagundo, whom Hoffman-Kim recruited for her lab in 2008 when she applied to Brown after graduating from the University of Puerto Rico, started the research with rigorous measurements of Schwann cells in cell cultures of rat neural tissue — the cell size, their elliptical shape, and the average distance between any two, as well as the length and width of the “processes” or wispy extensions that connect them.

“We were able to deconstruct the topography of Schwann cells,” said Lopez-Fagundo. “We were then able to manipulate it into different designs to better understand the influence this topography has.”

They came up with six archetypal designs. One of them mimicked the somewhat messy real-world layout of Schwann cells but the other five were arranged in neat horizontal rows. In one the elliptical Schwann cell bodies were few and far between. In another they were densely packed and in another their spacing was the exact average of Lopez-Fagundo’s measurements. Another design had no “processes” to connect the ellipses and another had only processes but no ellipses.

Using Brown’s microfabrication facility, Lopez-Fagundo patterned their designs on silicon wafers (like those used to make computer chips) and then transferred them to silicone squares about a centimeter on a side so that the ellipses and processes were in raised relief on the silicone. Then they put each pattern in a cell culture of rat neurons and watched them as the neurons grew across each pattern of artificial Schwann cells. As a control for their experiment, they also cultured cells on unpatterned silicone squares.

All of the patterns encouraged some directed neuron growth compared to the random growth of neurons on the unpatterned squares, but clearly some patterns did better than others.

After 17 hours, the two best patterns were the ones with only processes and the one with average ellipse spacing. The natural replica pattern and the one with only ellipses fared the worst.

But by day five, new winners emerged: the patterns where the ellipses were farther than average and nearer than average. Hoffman-Kim said she was surprised that the nerve cells didn’t remain content to follow the straightforward pattern of plain horizontal tracks formed by the process-only pattern. Meanwhile, to some extent, the neurons grew the proper way even without a continuous track at all, for instance in the ellipse-only pattern.

Lopez-Fagundo puzzled over the question of why the ellipses, also called “soma,” matter even as the neurons clearly also grow along the processes.

“I asked myself that question a lot and it wasn’t until I sat at the computer and looked at the [time lapse] videos over and over,” Lopez-Fagundo said. “They use the soma as anchor points. They jump from soma to soma and use the long axis of the soma to guide themselves.”

It’s as if the neurons navigated most effectively when they had both roads (processes) and rest stops (ellipses or soma) where they could get their bearings.

And thus the neurons made their way along the artificially optimized straight and narrow. To the researchers, who also included co-authors Jennifer Mitchel, Talisha Ramchal, and Yu-Ting Dingle, the experiments were a triumph of how the meticulous analytical control afforded by engineering can demystify a complex biological phenomenon.

“Sometimes when I give lectures I say, ‘Biomedical engineers are control freaks and we consider that a compliment,’” Hoffman-Kim said.