Sierra Services for the Blind, Reference: Science

Sierra Services for the Blind and Visually Impaired
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From Science News, July 2, 2005

SOUND OFF
With RNA interference, gene silencing roars into labs
BY CHRISTEN BROWNLEE

Although you don't hear a thing, there is a raucous party going on inside each one of your cells. Each minute of every day, molecules are murmuring information from one to the next in an ancient version of the game of telephone.

DNA, the genetic party host, starts each round by whispering a message to its chemical cousin RNA. Keeping the game going, RNA passes this communication to the ribosomes, the cell's amino acid_linking machines. They, in turn, spit out a protein translation of the original message. The proteins that result from this string of chatter fulfill all the cell's vital functions__and keep it going for countless more rounds of telephone throughout its life.

But what would happen if someone put a molecular muzzle on one of these players, disrupting a round of the game? It would muffle the influence of a particular gene. Such a tool would be a tremendous boon to scientists looking to discover that gene's function. Researchers could infer, by omission, the gene's role in a cell. Shushing unwanted messages could also provide medical researchers with a means to rid cells of proteins that cause diseases.

Scientists have spent decades searching for such a tool. One method, antisense RNA technology, proved to be unreliable. Another, engineering animals to lack a specific gene, can take at least a year. What's more, genes essential for life can't be studied with this knockout approach.

Eight years ago, scientists stumbled on a phenomenon called RNA interference (Rna_i). They've now developed it into a technique that many researchers suspect might be more useful than the other tools available forinactivating genes. RNA_I precisely targets a specific bit of RNA, effectively stifling its message before it makes a protein.

The tool, also known as gene silencing, doesn't actually turn the volume all the way down. Genes are muted at 90 to 95 percent efficiency, a state that scientists refer to as a knockdown.

For the past several years, the technique has been picking up steam. Scientists in thousands of labs are using RNA_I to determine the roles of particular genes in a variety of organisms. Other teams are using RNA_I to develop potential treatments for diseases including macular degeneration, AIDS, and Huntington's disease. "There's almost no field not affected by the discovery of RNA_I," says Phillip Zamore of the University of Massachusetts Medical School in Worcester, who studies the mechanisms by which RNA_I works. MOLECULAR MUTE__RNA_I got its humble start in the mid_1990's after researchers had witnessed some strange genetic behavior. Adding bits of DNA to some organisms, including fungi, plants, and worms, seemed to snuff out the activity of selected genes. A second set of odd observations came from researchers trying to block certain genes with the antisense method. In this technique, a complementary strand of RNA, the antisense strand, binds to part of a cell's normal, single_stranded RNA. When ribosomes encounter the resulting double_stranded bumps on a strip of single_stranded RNA, they don't translate those regions into proteins. This technique was applied to the roundworm Caenorhabditis elegans by several researchers, including Andrew Fire, then of the Carnegie Institution in Baltimore, Md., and now of the Stanford School of Medicine, and Craig Mello of the University of Massachusetts Medical School. The scientists soon had a mystery on their hands. Working together, Fire and Mello performedtests with copies of a cell's single_stranded RNA, which shouldn't bind to the cell's RNA because this so_called sense RNA isn't complementary to it. But sense RNA seemed to work just as well as antisense RNA does at muzzling genes. "We couldn't see a reason why sense and antisense would both work," Fire says. After puzzling over the phenomenon for months, Fire and Mello hit on an explanation. Both the sense and antisense samples that they had been injecting into C. elegans were contaminated by tiny amounts of double_stranded RNA (dsRNA). The researchers next tailored bits of dsRNA to match particular gene sequences. When the scientists deliberately injected the worms with that RNA, they effectively shut down those genes. The RNA_I technique was born. Over the next 7 years, Fire, Mello, and other scientists began deciphering RNA_I'S basic mechanism. Interference starts when a piece of double_stranded RNA, either present naturally in a cell or injected by researchers, bumps into an enzyme called dicer, which circulates inside a cell's fluid contents. As its name suggests, dicer acts like a samurai_wielding ninja. It chops the dsRNA into bite_size pieces of about 22 base pairs, the individual chemical blocks that make up RNA.

Each of these smaller pieces, called short interfering RNA'S (siRNA'S), then unzips into two RNA strands. One of these strands joins with a clump of several different proteins, the combination being dubbed an RNA'_INDUCED silencing complex (Risc). This complex then hunts down strands of RNA inside a cell that bind to, or complement, its siRNA strand. Once a complementary piece of RNA binds to RISC, several enzymes, including one named slicer, hack through and degrade it.

Since the viruses known as retroviruses often produce dsRNA while they're replicating, some researchers have proposed that dicer, slicer, and other components associated with RNA_I acted in early animals as a defense mechanism. This primitive type ofprotection, the theory goes, is no longer necessary in mammals and other organisms with complex immune systems.

However, modern cells seem to use RNA_I to control a wide variety of genes. Studies over the past few years have turned up dozens of RNA_I_LIKE mechanisms that affect, for example, embryonic development, stem cell activity, or virus assembly inside cells. "We've discovered a way that nature turns genes off," says Zamore.

CAN OF WORMS__SCIENTISTS are still figuring out the details of how RNA_I works. Zamore notes that a cadre of yet_unknown proteins, for example, seems to participate in each step of the process. But what's important, he says, is that RNA_I does work. During the past few years, thousands of researchers have used RNA_I to determine the functions of genes that were previously inaccessible to laboratory study. For example, one group is elucidating which genes are important for regeneration in planarian worms. These flatworms can fully regrow any amputated part of their bodies in just a few days, and an entire worm can regenerate from a tiny fragment of its body. A team led by Alejandro Sanchez Alvarado of the University of Utah Health Sciences Center in Salt Lake City recently used RNA_I to examine this process. By discovering how these worms regenerate, researchers may eventually find tools to improve wound healing in people. "Planarians have been around [in biological research] for about 200 years, and we've sliced and diced them in every conceivable fashion," says Sanchez Alvarado. However, the worms, which are frequently sterile, aren't suitable for traditional genetics studies, in which scientists breed organisms.

Sanchez Alvarado happened to be working at the Carnegie Institute when Fire and Mello made their pivotal RNA_I discovery."[Fire] surmised that I should be able to use these methods to make this genetically intractable organism tractable," Sanchez Alvarado notes. "It's worked extremely well." The May Developmental Cell describes his team's most recent efforts using RNA_I to find regeneration genes in planarians. Most of the worms' genome had already been sequenced. The researchers produced bacteria containing bits of dsRNA engineered to match an individual planarian gene and then fed that interfering RNA to a batch of worms. The RNA made its way into the worms' cells. The researchers repeated the process using each of 1,065 different bits of RNA and observed each bit's effect in silencing individual worm genes. About 145 of the silenced genes affected regeneration. Sanchez Alvarado and his colleagues now plan to determine how each of these genes operates.

Sanchez Alvarado notes that 38 of the other genes tested are related to human genes associated with diseases, including cancer. Only 8 of those 38 genes are currently under study in knockout mice. So, researchers using planarians may learn about gene functions that can't currently be studied in knockout animals. Muting genes with RNA_I holds advantages over creating knockout animals. While attempts to engineer animals free of certain genes sometimes simply kill them, animals that have a gene that's knocked down usually survive long enough to provide information about the gene's function, says Bryan Cullen of Duke University in Durham, N.c.

Greg Hannon of Cold Spring Harbor (n.y.) Laboratory says, "RNA_I will never replace knockouts, but what it does is it hugely expands the questions you can ask and the speed with which you can ask them." Hannon explains that creating a knockout mouse can take well over a year, while knocking down a gene with RNA_I takes only a few days. Furthermore, Hannon notes that scientistsdon't plan on tinkering with people's genomes by knocking out genes. Instead, RNA_I can silence a human gene in cells growing in lab dishes, enabling scientists to get a sense of the gene's role in the body.

To that end, Hannon and his colleagues have set up a library of RNA_I sequences at Cold Spring Harbor (n.y.) Laboratory that researchers can use to study gene function in mice and people. The library already has enough siRNA sequences to silence about two_thirds of the human genome and around half of the mouse genome. DICING DISEASE__APPLYING the new, reliable way to reduce activity of genes in human cells, researchers are now developing RNA_I_BASED drugs to quiet genes that cause diseases. The main prerequisite to developing an RNA_I_BASED solution is to learn which gene is problematic, says Fire.

Another limiting factor, notes Howard Robin of San Francisco_based Sirna Therapeutics, is getting the bits of interfering RNA inside cells and making sure the bits don't degrade before they do their jobs. "That is the huge challenge of developing these drugs," he says.

Many researchers predict that macular degeneration will be the first disease successfully treated with RNA_I. This currently incurable disease is a leading cause of blindness in older Americans. It obscures a person's straight_ahead vision when extra blood vessels grow, and then leak, in a central portion of the retina.

According to Robin, the retina is an ideal place for administering RNA_I. The retina is self_contained, so a drug injected there would remain where it needs to work. Moreover, retina cells easily take up bits of siRNA on their own.

Several companies, including Sirna Therapeutics and Cambridge, Mass._based Alnylam Pharmaceuticals, are currently developing RNA_I_BASED drugs for macular degeneration. Sirna recently wrapped up its first phase of experiments of its topdrug candidate. Each of 10 people with the disease received an RNA_I_CONTAINING solution injected into the eye. This treatment halted progression of the disease with no notable side effects. Five of these patients also improved their ability to read letters, a significant advance in treating macular degeneration.

Clinical trials will also be under way next year for an RNA_I_BASED drug to treat HIV, the virus that causes AIDS. John Rossi of City of Hope, a medical_research center in Duarte, Calif., is now testing the drug in mice. The treatment prompts immune cells to produce siRNA that shuts down critical viral genes. Without the activity of these genes, the virus can't replicate and spread through the body. In experiments with human blood cells growing in the laboratory, the intervention "works like a charm," says Rossi. "It basically blasts away at the virus."

Researchers are making steady advances in work on several other diseases, including neurological disorders, although RNA_I_BASED therapies there probably have a long way to go before they reach the clinic. For example, Beverly Davidson of the University of Iowa in Iowa City has developed a strategy to use RNA_I to treat Huntington's disease, which chips away at a person's ability to walk, talk, and reason. The fatal disease results from production of a mutated protein that's toxic to some types of brain cells. Davidson and her colleagues created genes that produce a type of RNA_I that blocks production of the toxic protein. The researchers shuttled those genes into the brain cells of mice that develop a version of Huntington's. The mice have since shown a dramatic improvement in symptoms. Davidson notes that these results are somewhat surprising because this intervention knocks down the mutant proteins by only about 60 percent, making the payoff remarkable. "We got a lot for a little," she says.

Even with these promising successes, manyresearchers don't expect RNA_I to provide a quick fix for many health problems. Fire predicts years of ups and downs as scientists learn the potential of RNA_I. "I think there will be failures and successes in trying to get these therapeutics to work," says Fire.

Nevertheless, says Robin, "I think we're making excellent progress." With so many researchers turning to RNA_I, this field is now moving swiftly__and not so silently__ahead. Picture Captions: AS THE WORM TURNS__A normal planarian glides over a composite background of defects that scientists generated by applying the technique of RNA interference to other planarians. STEP BY STEP__RESEARCHERS have identified several basic stages in the mechanism of RNA interference. 'These are the steps shown in print.' Double_Stranded RNA (dsRNA) dsRNA Processing by Dicer Short Interfering RNA (siRNA) siRNA Unzips RNA_InDUCED Silencing Complex Complex Binds to Complementary RNA RNA cleavage RNA Degrades

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Chip may serve as artificial retina

Stanford University School of Medicine recently put on their web site the latest on their study of using a microchip to replace retinal function. The Stanford Ophthalmic Tissue Engineering Laboratory study, directed by Harvey A. Fishman, MD, Ph.D., differs from other micro ship studies in that their chip assists the body in the release those chemicals which emulate normal function. To quote the study, "The team built a computer chip with four tiny openings, and used it to control the environment of neuron-like cells. The chip exuded droplets of chemicals using electro-osmosis. …The chip also withdraws fluid wen needed, which could prevent a potentially toxic buildup of the chemicals." This is particularly promising for age related macular degeneration. Dr. Fishman described how it works, "It’s almost like an ink-jet printer for the eye."

For more information, contact the Stanford School of Medicine

Posted 11/22/04

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"It is estimated that 200 thousand eyes in the United States are annually blinded by macular degeneration". Kamil Z. Skawinski, California Computer News, January 2003 Kamil Skawinski researched the newest technology related to the recovery of vision for California Computer News. Two things emerged from his study of the issue. First was what technologies are being worked on, and second the scope and breadth of the problem of vision loss in the United States.

Skawinski found medical solutions within the computer industry, which are far down the road. While fascinated with the technology surrounding the vision research industry, he found them very early in their stages of development.

Clinical trials are now being conducted by Optobionics for an Artificial Silicone Retina. (WWW.Optobionics.com) . This silicone chip is thinner than a human hair, and is implanted in the retina. It has approximately 5,000 microscopic solar cells, or microphotodiodes. Each has a stimulating electrode designed to convert light energy to electrical impulses to stimulate the remaining functional cells for those with pigmentosa or macular degeneration. Sandia National Laboratories and others are developing another use of microchip technology. Mark Humayun developed the Sandia project, which uses sensors, first at Johns Hopkins. He then formed the Interoculare Retinal Prosthesis Group at Doheny Retina Institute at the University of Southern California, where the system will be tested.

Artificial vision systems are also being developed. The "Dobelle Eye" is one of a few television-based systems being developed. This one takes the image, and after processing transmits it directly onto the brain with 68 platinum electrodes implanted on the surface of the visual cortex of the individuals brain. This is made possible by new techniques of reducing infection around wires, which penetrate the skin.

These systems are all decades off both from the research and trial periods they require, but from the cost factors as well. It will take decades before they are as common as a hearing aid.

There is also some work with stem cells and the regeneration of the eye itself. Eyes have been grown on frogs in Japan as one instance. However, like all stem cell research, the solution is decades off.

His fascination for technology caused Skawinski to stumble on to the gravity of the problem first discovered by Dr. J. E. Crews of the University of Mississippi in 1988. While he did not discover Dr. Crews, his understanding shows he was impressed by the number of people affected by the problem of vision loss. Skawinski started his article in the California Computer News with a statement of the problem rather than the usual "Ain’t this wonderful" technology part of the article.

Dr. Crews found that one in four would become legally blind by macular degeneration alone at age 80. He also found that those elderly who become blind are 3 times more likely to have difficulty walking or getting out of a chair or bed. The effects are a dramatic increase in senior health issues from arthritis, or the simple act of being able to prepare a meal. They are twice as likely to have arthritis or cardiovascular disease, and 6 times more likely to have trouble getting outside.

The results have national implications to our aging population. Of the 25% who are blinded by macular degeneration, 20% of those are placed in long term care institutions. While 5% of the total senior population is in long-term facilities, 46%of them have vision problems, second only to ambulation.

The figures quoted do not include diabetes related vision loss, pigmentosa, or any of the other causes for vision loss. Another recent discovery is that smokers are two and a half times more likely to lose vision, and more likely to lose their sight than have lung cancer than non-smokers. Three studies published in the Journal of the American Medical Association, two in Europe and one in the United States showed amazingly consistent results on smoking and vision loss. They also found that individuals who had stopped smoking as long as twenty years earlier were equally affected. These figures were used as a part of the process for dissemination of tobacco settlement money. However, it can only be used for education, not treatment and education for those who have lost vision.

As a nation we will spend in excess of $9.5 billion on institutionalizing the blind by the year 2020. Dr. Crews found that seniors on average expend their personal resources after an average four months, and then must be cared for at public expense. We are now expending an average of only $2.22 per year per elder blind for education, counseling, and transportation to medical appointments, and other programs to keep the individual independent and out of the public care system. Sierra Services for the Blind spends around $300 per year keeping their elderly clients independent and out of the public system. In their region alone, the minimum cost for one year of public expense long-term care housing alone is $24,000.

If a person has a stroke, they are entitled to complete services for rehabilitation in our present system. If they lose vision they are on their own to quote Dr. Crews, "While there is a designated state rehabilitation agency in each state, there is no national entitlement rehabilitation program designated for all elders who are blind. In other words, being blind does not mean that an individual is automatically "entitled" to federal or state rehabilitation services. Simply put, most elders who are blind are on their own."

Even within the state systems the blind are left out. If you require a wheel chair, or even a car modified for use if you use a chair, state rehabilitation will provide it. These "mechanical fixes" do not work if you are blind. If you need magnification, a talking computer, or other items, rehabilitation will only pay for them through special processes handled by the general rehabilitation department. In California, if they do provide equipment such as a talking computer, they will not provide the education on how to use it. In 26 states blind services were separated from the general rehabilitation departments and in all 26 cases the amount of services performed with the same dollars doubled in the first year. This is why every major city has a separate agency for the blind from those agencies that claim to work with all disabilities. At the same time, a study by the Lighthouse in New York found Sierra Services for the Blind in Nevada County California the only full service agency for the blind serving in exclusively a rural community in the nation.

Rural communities often have the largest senior populations. Nevada County California has the largest percentage population of seniors in the state at over 30 percent, and the largest percentage over age 85. Thus, they likely have the largest concentration of senior blind in the state. They are not funded by either state or federal funds, and receive only 7% of their funding from County sources.

Again to quote Dr. Crews, "This is not a cyclical change in our society, it is a structural change. Our society is aging, and with it will come specific medical issues which we must face. The financial resources that will be required to accommodate health related problems associated with blindness, and the premature institutionalization now documented, must be addressed. So too, the cost in human terms to the both the individual and the family."

Remember also, someone who is over eighty and is blind likely has children who are in their sixties. This is a generation who went through the Great Depression, and when they say they will "get by", they mean it. They don’t what to be a burden, either to their children, or the government. It has been said that if truth were out, complications of starvation is the number one cause of senior death. It just becomes too painful to make that meal; it is not worth the effort to cook a complete meal for one, especially if you can’t see that well. You don’t have to be blind to have visual impairment become a threatening health issue.

What this means is that we need to deal with the issues raised by Dr. Crews. The Baby Boomers will arrive long before there is a medical fix, and the cost in both financial and human terms will be far greater than the cost of educating and supporting the independence of those now losing their sight. The adjustments needed are amazingly simple, and the payoff is far greater than the cost in dollars could ever match with the present institutionalization system we now embrace.

Another caution is that agencies centered around large cites, and national organizations such as NFB, AFB, Lighthouse and others tend to develop programs around agency need rather than client need. They hold a class, and the individual must attend. Rarely is transportation provided even though the blind can not drive, and is not provided or even available if you are "out of town". When they are done with "the program", they are no longer followed to see of the education worked for them. Those institutions charged to keep the blind out of institutions are often becoming institutions themselves.

As seniors lose vision slowly, the needs change, and so too must the program designed to fill their need for education and support. An agency like Sierra Services for the Blind which designs a program around the individuals need, must have virtually 386 programs for 386 people. While some are peer groups which serve the group need and client management functions, and larger community based programs for education and access, they are not time related. They have no end which says you are done, go home. It is not as unmanageable as you would think, for the purpose is to help the individual manage their own independence.

Like most agencies serving those whom have lost their sight, Sierra Services would love it if technology and medicine would make their services obsolete. Until then, and unfortunately it will be after the baby boom generation has passed, services for the blind will be done through counseling, education and personal contact. It is a human problem, which requires a human touch.