Eye gene: Researchers have found a genetic link between a molecule involved in immune response and a common form of macular degeneration. When tlr3 is activated by genetic expression, it causes cell death similar to macular degeneration in areas of mouse retinas, indicated by the arrows.
Credit: Kang Zhang/UCSD

A key molecule related to immunity may play a role in macular degeneration.

MIT Technology Review, by Jennifer Chu — Age-related macular degeneration is the leading cause of blindness in people over the age of 65, and it affects more than 10 million people in the United States. The disease erodes the macula, the center of the retina, slowly eclipsing central vision and potentially causing blindness. Currently, there is no treatment for dry macular degeneration, the most common form, in which more and more cells within the macula slowly die off.

Now a team of researchers from multiple institutions, including the Shiley Eye Institute, at the University of California, San Diego (UCSD), have identified a genetic link associated with dry macular degeneration, which they say may lead to treatments for the debilitating disease. However, they caution that an experimental therapy for another form of macular degeneration may cause adverse effects in patients who possess the genetic variant.

Kang Zhang, a professor of ophthalmology and human genetics at UCSD, led the study, which is published in the online edition of the New England Journal of Medicine. In their experiments, Zhang and his colleagues zeroed in on the genetic expression of a key molecule involved in the body’s immune response. This molecule, called tlr3, jumps to action in the presence of RNA, which can take the form of invading viruses. As part of the immune response, the molecule kills infected cells, preventing the virus from spreading further. But in some cases, this defense can go haywire in the eye.

The molecules’ “role in life is to kill cells to protect the universe around healthy cells,” says Nico Katsanis, Zhang’s collaborator on the study and an associate professor of ophthalmology, molecular biology, and genetics at the Johns Hopkins School of Medicine. “But if they are too sensitive towards viral insults, they might kill cells a little too eagerly, and that might be a predisposing factor that leads to macular degeneration.”

The group hypothesized that a gene that increases the activity of tlr3 may in fact lead to overeager cell death in response to RNA and viruses, and it may increase a person’s risk for dry macular degeneration.

To investigate this potential link, the team first performed a genetic association study, and obtained blood samples from three groups of patients, each with a different form of macular degeneration, including those with wet macular degeneration, a severe form characterized by an overgrowth of blood vessels behind the retina. The researchers also included more than 300 samples of unaffected controls.

After doing DNA analysis of the samples, the group identified a genetic variant that promotes low tlr3 activation. Patients possessing this variant were in a sense genetically “protected” against dry macular degeneration, whereas patients with a variant that promotes high tlr3 activity were 20 percent more likely to develop dry macular degeneration.

Since tlr3 is activated in response to RNA, Zhang says that this genetic association may raise concerns over RNA-based therapies for wet macular degeneration. Currently, clinical trials are under way for RNAi therapies to treat wet macular degeneration and turn off the genes responsible for blood-vessel overgrowth in the eye. However, Zhang says that these RNA-based therapies may have adverse effects for people with the genetic variant that increases tlr3 activity. In essence, the otherwise therapeutic RNA would trigger tlr3 to kill cells in the retina, which could ultimately lead to vision loss.

“We are able to see if we can develop a therapy to modulate or inhibit tlr3 to treat dry macular degeneration,” says Zhang. “Also, people undergoing RNAi therapy need to be aware of potential harmful effects of tlr3 activation.”

However, Rando Allikmets, director of the molecular-genetics laboratory at Columbia University, says that, compared with other genes associated with macular degeneration, the tlr3-linked association that Zhang found is not very strong, and should not have much effect on RNAi therapies. “Their data shows that [tlr3] is technically associated with dry macular degeneration,” says Allikmets. “But even if there is something, 20 percent risk [of dry macular degeneration] is very, very minor.”

More likely, Katsanis says, the group’s findings may illustrate a masking effect for otherwise beneficial RNAi therapy. For example, patients who unknowingly overexpress tlr3, and who are treated with RNAi therapy, may still experience the positive effects of RNA, but also the negative effects of cell death. The overall effect may be no effect at all.

“The genotype may counterbalance beneficial effects of RNAi treatment, and the final analysis may be that this treatment is noneffective, and you may be throwing away a perfectly good treatment,” says Katsanis. “What this says is, potentially, people with the right variant might be better candidates for RNAi therapies, and vice versa, and we may target disease more effectively according to genotype.”

Hope in sight: A new imaging technique could detect eye disease before if affects vision.
Credit: Technology Review

A new technique could be used to diagnose and treat patients before they begin to go blind.

MIT Technology Review, by Anna Davison — State-of-the-art imaging equipment is being used by researchers at the University of Michigan to spy on cells in the eye in order to detect eye disease at a very early stage. They say that their technique could pick up signs of serious problems, such as glaucoma, early enough for patients to be treated before their vision is affected.

The researchers’ method looks for metabolic changes in the cells of the retina and optic nerve due to disease. Those effects begin long before the first obvious signs normally hit, such as vision loss or structural abnormalities.

Using a sophisticated camera system coupled with customized imaging software, the researchers were able to detect changes in the eyes of patients with a brain disorder that can affect the optic nerve, and in people with glaucoma and diabetic retinopathy, two of the most common causes of blindness.

“We believe that this is going to be useful in a variety of diseases that affect the eye,” says Victor Elner, an ophthalmologist and pathologist at the University of Michigan. The new test takes less than six minutes, and Elner says that it could be developed as a “point and shoot” system in which images are analyzed on a computer, either in an ophthalmologist’s office or at a centralized location.

If the technique proves effective, “it could provide an early warning that cells have become sick,” says Joseph Rizzo, a neuro-ophthalmologist at the Massachusetts Eye and Ear Infirmary, who was not involved in the work. That would allow physicians to start aggressive treatment before patients begin to go blind. If they are treated early, progressive eye diseases like glaucoma can be controlled, which slows or prevents damage to the eye and preserves vision. “It’s potentially truly wonderful,” Rizzo says of the detection technique.

In a study reported in the current issue of Archives of Ophthalmology, Elner and four colleagues at the University of Michigan tested their imaging technique on six women who had recently been diagnosed with a condition called pseudotumor cerebri (PTC), a disorder in which a buildup of pressure in the brain causes symptoms similar to those of a brain tumor. In some PTC patients, pressure on the optic nerve can lead to vision loss.

The researchers began by administering standard vision tests to the women. They all had good visual acuity. Visual field testing, which measures the area seen by the eye and is routinely used to screen for diseases like glaucoma, indicated subtle abnormalities in some of the women.

Elner and his colleagues then used their new metabolic imaging system to check the health of cells in the women’s eyes by shining a blue light on their retinas and looking for green fluorescence given off by oxidized proteins in dying cells. They measured the intensity of this fluorescence and found that it was significantly greater–60 percent, on average–in the eye that was most affected by the disorder. There was no significant difference between the measurements in the eyes of women without PTC. “Diseases seldom affect both eyes the same,” Elner says. “We generally pick up an asymmetry in all kinds of diseases.”

The new technique proved as effective as, or often superior to, the standard tests performed on the women. Elner and his colleagues are also studying the method in patients with glaucoma, which damages the optic nerve, and diabetic retinopathy, which involves changes in the blood vessels in the retina, but they have not yet published the results of those studies.

“This technique is intriguing,” says Sunil Srivastava, an assistant professor of ophthalmology at Emory University’s Eye Center, who was not involved in the work. “There’s a lot of potential for it.” But, he says, “what’s needed is going to be lots of data looking at patients with early disease, and following them with it.”

Because the new imaging system could be used to track metabolic changes in the cells of the eye, Elner believes that it may also be useful in drug discovery. The effects of potential treatments could be tracked over weeks, he says, rather than having to wait months to observe changes in vision, or in the structure of the eye.

“This will be a faster method of screening for drugs,” Elner says.

It could also enable physicians to closely monitor the effect of drug regimes on their patients, he adds, so that they can figure out the very best treatment strategy.

Credit: Technology Review

A novel medical device could treat eye diseases like age-related macular degeneration.

MIT Technology Review, by Amanda Schaffer — In September 2008, the U.S. Food and Drug Administration fast-tracked a novel treatment for two eye diseases: age-related macular degeneration and retinitis pigmentosa. The treatment, developed by the Lincoln, RI, biotech company Neurotech, is a capsule that’s surgically implanted in the eye. Inside the capsule are genetically engineered cells that produce a protein that may prevent light-sensitive cells in the retina from dying–thereby protecting vision. The device is currently in phase II clinical trials.

Neurotech’s platform is “unique” and “fills a significant void in treatment options for retinal degenerative diseases,” says Stephen Rose, chief research officer at the nonprofit Foundation Fighting Blindness, which has given grant money to Neurotech but does not have a financial stake in it. “To my knowledge, no other company is testing a similar device,” Rose says.

Normally, cells in the back of the eye–the retina–translate light into electrical signals, which are relayed to the brain. In both retinitis pigmentosa and the most common form of age-related macular degeneration, dry AMD, light-sensitive cells in the retina degenerate over time. This results in loss of vision.

Patients with these diseases currently have few or no treatment options. To date, no drugs or devices have been approved for retinitis pigmentosa or for dry AMD, says Rose. (A drug called Lucentis is available for a less common form of macular degeneration, called wet AMD, which is characterized by the leaking of blood vessels.)

Neurotech’s device is implanted in a part of the eye called the vitreous humor, a transparent gel that lies between the lens in front and the retina in back. The capsule is made of a semipermeable plastic, which allows the protein produced by the genetically engineered cells to diffuse into the retina. In animal studies, the protein–ciliary neurotrophic factor, or CNTF–slowed the degeneration of retinal cells in diseases analogous to retinitis pigmentosa. According to Weng Tao, chief scientific officer of Neurotech, there’s even evidence that CNTF could promote retinal regeneration.

Implanting a device in the vitreous humor is relatively easy, says Peter Francis, an ophthalmologist and expert in retinal disease and ophthalmic genetics at the Casey Eye Institute in Portland, OR. It’s a procedure already used, for instance, with devices that release steroid molecules into the eyes of patients with intraocular inflammation. But because Neurotech’s device contains cells, it offers the prospect of longer-term treatment. At least in theory, those cells should continue to release CNTF as long as they remain alive.

So far, Neurotech’s approach appears to be safe for patients with degenerative diseases of the retina. That was the finding of a phase I trial with 10 patients, the results of which were published in 2006. “The real challenge is whether we’ll be able to translate the positive observations in animals in humans,” says Tao. The phase II trials, which Tao says should conclude by early 2009, are intended to answer that question.

Neurotech’s is not the only approach to combating degenerative retinal diseases, however. Other researchers are transplanting various kinds of cells into the retina itself. For instance, Thomas Reh, a biologist and expert in retinal-cell development and regeneration at the University of Washington, has used embryonic stem cells to produce light-sensitive cells, which resemble those of the retina. His team is now transplanting the cells into the eyes of blind mice to see whether they improve the animals’ sight. In related work, Advanced Cell Technology, a biotech company based in Alameda, CA, has used embryonic stem cells to produce another type of retinal cells–called pigment epithelial cells–that degenerate in macular degeneration. When transplanted into animal models, these cells appear to protect the light-sensitive cells of the retina and improve vision. Still other researchers are working with cells derived from fetal tissue.

In these approaches, the goal is to integrate new cells into the retina to help restore its function. Rebuilding parts of the retina might result in more dramatic or long-lasting improvement than simply slowing degeneration, says Reh. On the other hand, Neurotech’s strategy “may be less risky because if something goes wrong, you can get the cells out again” simply by removing the device, he says.

Neurotech is also farther along in the clinical-trials process than any other cell-therapy group, so its platform could be available to patients sooner, Reh adds.

Other active research involves gene therapy. For example, Ceregene, a biotech company based in San Diego, is working with the gene for a protein called NT4. Researchers at the company have introduced the gene into the retinas of several animal models and seen improvements in vision, according to Jeffrey Ostrove, president and CEO of Ceregene. The company expects to begin clinical trials in people with retinitis pigmentosa and macular degeneration soon, possibly in 2009.

Rose, however, emphasizes that Neurotech offers more than just a specific treatment regimen; it also offers a novel drug delivery system. “Even if the results of the current trials aren’t 100 percent spectacular,” he says, Neurotech’s approach could be adapted to deliver other growth factors or therapeutic molecules down the road. “That’s the beauty of it. It’s a spectacular platform

Retina revitalized: A regenerated amacrine cell, which is a type of cell found in the inner retina. The nucleus of the cell is labeled in red, while the rest is labeled in green.
Credit: Thomas Reh

Researchers stimulate the growth of new retinal cells in mice.

MIT Technology Review, December 9, 2008, by Amanda Schaffer — Cells in the retina of mice can be coaxed to create new neurons following an injury, according to new research from the University of Washington. This is the most definitive demonstration to date that such regeneration is possible, given the right cues, for a specific type of neuron in the inner retina of a mammal.

If researchers could spur the development of different types of new neurons in the living human eye, they might be able to replace cells that are lost in diseases like macular degeneration and retinitis pigmentosa. Few or no treatment options are currently available for patients with these diseases.

“This is an excellent, clear demonstration that you can regrow cells of the inner retina,” says Stephen Rose, chief research officer at the nonprofit Foundation Fighting Blindness.

The retina, which is located in the back of the eye, has an outer layer of cells that detect light and translate it into electrical signals. It also has inner layers, which process the signals and send them to the brain.

In degenerative disorders like macular degeneration and retinitis pigmentosa, outer-layer cells, called photoreceptors, break down in the early stages of disease, leading to loss of vision. Extensive research has focused on replacing these cells, in an effort to restore sight. In people with advanced disease or blindness, however, the inner cell layers may also break down or become disorganized and need to be rebuilt, says Rose.

“The outer retina is like the CPU, and the inner retina is like the motherboard,” he says. “If I attach a new CPU to a dead motherboard, it won’t do any good, no matter how great a CPU it is.”

In the current work, developmental biologist Thomas Reh and his team first damaged the mice’s retinas, using a chemical known to destroy inner retinal cells. Then they injected a cocktail of proteins called growth factors. This process spurred some cells, called muller glia, to return to an immature state. Muller glia normally provide nutrition to other neurons and do not divide. Following chemical treatment, however, some of them returned to an undifferentiated state in which they resembled progenitor cells.

The immature cells then started to proliferate, some of them differentiating into mature neurons. In particular, they formed amacrine cells, which are located in the inner retina. These cells mediate electrical signals coming from the photoreceptors and are particularly important to motion detection and night vision, says Reh.

“We did not get a large number of new neurons,” he adds. “But we showed that we could make new amacrine cells, the cell type that had been lost to damage.” The findings were published this week in the online edition of the Proceedings of the National Academy of Sciences.

The current work may help build a foundation for future therapies in which cells of the inner retina–and potentially other cells, including photoreceptors–are regenerated in situ, in the living human eye, says Reh. In theory, such treatments might allow physicians to replace retinal neurons “precisely at the spot where they’re needed, without disruptions or discontinuities,” he says.

In lower vertebrates like fish and chickens, retinal cells are known to generate new neurons in response to damage, often restoring sight. While mammals do not have the same self-healing capacity, some previous research has suggested that under particular circumstances, mammals’ retinas might be able to generate new neurons. Reh’s current work offers more definitive evidence that immature cells, derived from muller glia, can differentiate again into mature neurons, says Michael Young of the Schepens Eye Research Institute.

More research is needed before retinal regeneration can be attempted in humans. “We need much more control over the basic cellular processes”–trying to regenerate different types of neurons and making sure that they function properly in vivo–“before we can treat real people with blinding disease,” says Anand Swaroop of the National Eye Institute.

For example, scientists need to show that regenerated neurons behave normally in the eye, integrating into circuits with other cells and contributing to vision. “It is hard enough to grow different cell types,” says Rose. “But will they function? Will they do what the cells they are replacing normally would do? That’s really tough.”

Reh says that growing new cells in the eye could be preferable to transplanting cells, an approach that his team is also working on. “Transplantation involves a tricky surgery; the cells may not go exactly where you want them to go,” says Reh, and some cells could cause an immune reaction. “Developing methods to stimulate regeneration may prove to be the best option in the long run.”

Enhanced vision: Researchers at the Schepens Eye Research Institute have developed software that lets users enhance the contrast of images on a television screen. In the image above, the screen is split: on the left is an unenhanced television picture, and on the right is a picture with the contrast enhanced.
Credit: Schepens Eye Research Institute

Using a new algorithm, researchers are trying to enhance picture quality so that those with macular degeneration can enjoy TV.

MIT Technology Review, by Brittany Sauser — Enjoying a favorite TV show can be difficult for someone with macular degeneration. Like many kinds of visual impairments, macular degeneration makes the images on the screen seem blurred and distorted. The finer details are often lost. Now researchers at the Schepens Eye Research Institute have developed software that lets users manipulate the contrast to create specially enhanced images for those with macular degeneration.

“Our approach was to implement an image-processing algorithm to the receiving television’s decoder,” says Eli Peli, a professor of ophthalmology at Harvard Medical School and the project leader. “The algorithm makes it possible to increase the contrast of specific size details.”

The researchers focused their work on patients with age-related macular degeneration, a disease in which the macula–the part of the eye that’s responsible for sharp, central vision–is damaged. According to the American Macular Degeneration Foundation, more than 10 million Americans suffer from the disease, which often leaves those afflicted with a central blind spot. A patient’s remaining vision is often blurred, making it extremely difficult for people to watch television or even read the paper, says Mark O’Donoghue, clinic director of the New England College of Optometry’s Commonwealth Avenue Clinic. “This is really new and fascinating to read about,” says O’Donoghue. “I recognize the basic facts in the technology and the path of physiology in which [Peli] is doing this, and it is innovative.”

Peli and his group currently have the new software running on a computer in their lab, but they’re expecting to receive a prototype system built by Analog Devices in April 2008.

Peli’s group discovered that patients suffering from macular degeneration could not perceive high-frequency waves in the visible spectrum, which left them unable to see fine details.

In order to give the patient a much better chance of discerning the image, the researchers designed an algorithm that specifically increases the contrast over the range of spatial frequencies that the visually impaired could see: the middle and low frequency waves. Ultimately, Peli says, the system enhances the contrast of the picture, and the result is that the finer details are more evident.

The contrast can be adjusted by a user in much the same way that one would change the volume on a TV using a remote control. O’Donoghue likens the system to a stereo equalizer for the eyes that allows TV watchers to fine-tune the picture.

To measure the amount of image enhancement that individuals prefer, the researchers recently conducted a study using 24 patients with visual impairments and 6 normal-sighted people. The subjects sat in front of a television and watched four-minute videos, adjusting the level of contrast with a remote control. The researchers found that all the subjects–even the normal-sighted people–wanted some level of enhancement, and the majority of the time a subject chose the same level of enhancement whether they were watching a dark scene or fast action, says Peli. (The amount of enhancement selected correlated to the severity of the subject’s vision loss.) The study was published last month in the Journal of the Optical Society of America.

One day, this system could transform watching TV alone or with the family into a more “rewarding experience” by making it easier for people to pick out the objects of interest from their surroundings, says Tom O’Donnell, an assistant professor at the University of Tennessee’s Hamilton Eye Institute.

Peli hopes that the system will eventually be incorporated into the menu options for all televisions. Ideally, people will have the option to see an enhanced view just as the hearing impaired have the option to call up captions, he says.

Credit: Phaedra Wilkinson

Scientists are developing new ways to manipulate the brain’s normal plasticity.

MIT Technology Review, December 9, 2008, by Emily Singer — New ways to manipulate neural plasticity–the brain’s ability to rewire itself–could make adult brains as facile as young ones, at least in part. Drugs that target these mechanisms might eventually help treat neurological disorders as diverse as Alzheimer’s, stroke, schizophrenia, and autism. But first scientists will need to figure out how to harness this rewiring capacity without damaging vital neural circuitry.

“Once we understand the mechanisms behind plasticity, we can design therapies to tap into it more specifically,” says Joshua Sanes, a neuroscientist at Harvard Medical School.

The brain experiences a “critical period” of heightened malleability during development, when outside experiences–such as sights and sounds–are necessary for different brain systems to develop normally. Infants and toddlers between the ages of one and three need regular visual stimuli, for example, in order for their visual systems to form the appropriate neural circuits. If one eye is impaired during this time, such as with lazy eye (also called amblyopia), vision may be permanently faulty.

Studying the equivalent of lazy eye in rodents, Takao Hensch and his colleagues at Children’s Hospital Boston discovered two mechanisms that control this critical period. While some drugs were already known to accelerate the onset of this critical period–for example, valium, an anxiety drug that targets the brain’s inhibitory signaling system–Hensch’s work helps explain why and provides specific targets for new treatments.

Like children, rodents with one eye covered during their critical period never recover normal sight. Scientists use this fact to measure treatments that affect the timing of developmental neural plasticity. Treatments that extend the critical period, for example, allow adult animals reared with only one functioning eye to regain normal sight. Hensch’s group has previously shown that a specific cell type, called a large basket cell, triggers the onset of neural plasticity. These cells are surrounded by molecular nets. “The critical period ends when the net wraps around [the cells] very tightly,” says Hensch. So molecularly severing the nets with an enzyme called chondroitinase can restore plasticity in adults.

Hensch and his collaborators have now found that basket-cell development is controlled by a protein called Otx2. Overexpressing this protein can trigger a critical period of plasticity, while removing Otx2 halts it. While the findings are specific to the visual system, Hensch notes that different sensory systems also possess basket cells, and those might function the same way.

A second mechanism for manipulating neural plasticity in adults is blocking inhibitory molecules that the nervous system produces to stop neural growth. “The nervous system is hostile to growing new axons [the long neural projections that connect cells], which is why recovery after spinal-cord injury is so challenging,” says Hensch.

Myelin cells, which form an insulating layer around axons, secrete some of these inhibitory molecules. By experimenting with certain drugs that loosen myelin, Hensch and his collaborators found they could make the normally stable visual system of adult rodents become plastic again, allowing amblyopic rodents to recover. (However, the drug used in the study is toxic, making it unlikely to be a useful therapy.)

Given the usefulness of recapturing the neural facility of youth–the ability to quickly learn a new language, for example–it may seem odd that the brain would have evolved multiple mechanisms for preventing major rewiring in adults. But the capacity to easily overhaul neural circuits could have a downside, perhaps erasing memories. “You might lose the identity you’ve built,” says Hensch. “We want you to be able to keep what you know.”

To successfully co-opt the plasticity of youth, scientists will likely need to target treatments very precisely. “Maybe we can do a careful release of the critical period,” says Alison Doupe, a neuroscientist at the University of California, San Francisco, who was not involved in Hensch’s research. For example, “maybe you could turn on [plasticity] only when learning Russian.”

In addition to suggesting ways to enhance mental agility in old age, the findings may provide a new explanation for developmental disorders, such as autism.

Scientists have recently discovered that several strains of mice genetically engineered to mimic rare inherited forms of autism have an imbalance in levels of excitatory and inhibitory neural signals. Hensch’s previous research suggests that this kind of imbalance can throw the critical period out of whack. “Maybe different brain regions become plastic too early or too late [in autism],” says Hensch. That might also explain why disruptions to such different molecules can trigger similar symptoms, he says. “Maybe they have a common wiring problem.”

The researchers are now studying these imbalances in greater detail. For example, they found that mice from one of the strains, genetically engineered to show symptoms of autism, have too many neural connections in a specific part of the brain, although each connection is individually weak. “That could lead to too much variability,” says Hensch. “Maybe we can use that property to repair the circuit.”

Double agent: The SIRT1 protein (red), long associated with age-related disease, clusters around chromosomes (blue) in the nucleus of a mouse cell. In young organisms, SIRT1 effectively doubles as a gene-expression regulator and a DNA repairer. But when DNA damage accumulates—as it does with age—SIRT1 becomes too busy fixing broken DNA to keep the expression of hundreds of genes in check. This process is so similar to what happens in aging yeast that its discoverers believe it may represent a universal mechanism of aging.
Credit: Philipp Oberdoerffer

Parallels between mice and yeast uncover a potentially universal aging mechanism.

MIT Technology Review, December 9, 2008, by Jocelyn Rice — Elderly mice and aging yeast have more in common than scientists ever suspected. A new study by Harvard Medical School researchers reveals that the biochemical mechanism that makes yeast grow old has a surprising parallel in mice, suggesting it may be a universal cause of aging in all organisms.

“It was very exciting when we made the discovery, because it was so unexpected,” says David Sinclair, a Harvard Medical School professor of pathology and senior author of the study, published today in Cell.

In yeast, aging–marked by an inability to continue replicating–is modulated by a protein called Sir2, which has counterparts, called sirtuins, in nearly every known organism. Normally, yeast Sir2 attaches to repeating DNA sequences to keep them stable. It also doubles as a DNA repairer, migrating to damaged spots on the genome and helping to patch them up. When a yeast cell is young, DNA damage is minimal, and Sir2 can keep up both these roles. But as the cell ages and accumulates more and more DNA damage, Sir2 becomes too busy with repairs to consistently stabilize those volatile repeating sequences. Left unsupervised, the repeats recombine into little extrachromosomal loops of DNA that build up and prevent the cell from reproducing.

This mechanism was discovered a decade ago in the MIT lab of Leonard Guarente, where Sinclair was then a postdoctoral researcher. For years, says Sinclair, few scientists suspected it had any relevance for understanding the process of aging in humans or other mammals. Although sirtuins have been linked to aging in a wide variety of organisms, their mechanism of action was understood only in yeast. But now it seems a remarkably similar process may underlie aging in mice as well.

One function of the mouse version of Sir2, called SIRT1, is to regulate how genes are expressed in various tissues. Patterns of expression differ among organs–many genes that need to be active in the liver, for instance, must remain silent in the brain. By binding to regulatory regions alongside certain genes, SIRT1 helps dictate those patterns. Because SIRT1 has also been shown to participate in DNA repair, Sinclair and his colleagues wondered whether increasing DNA damage would compromise the protein’s normal regulatory role, as is the case with Sir2 in yeast.

Sure enough, when the researchers treated mouse embryonic stem cells with DNA-damaging hydrogen peroxide, SIRT1 migrated away from regulatory regions of the genome and toward the many areas where DNA strands had broken. As a result, genes that were normally shut off suddenly became active. Gene expression patterns, once exquisitely fine-tuned, went haywire.

“This is something that’s eerily parallel to what we know in yeast,” says Jan Vijg, chair of genetics at Albert Einstein College of Medicine, who was not involved in the study.

Yeast are the only organism in which the mechanism of aging is well understood, says Sinclair. “We only know for sure why yeast age,” he says. “[With] all the other organisms, it’s still a black box. But we’re hoping that this is an explanation for all organisms.”

Guarente agrees that the resemblance to yeast is surprising. “It was interesting to see this commonality,” he says. “The degree to which it recapitulates yeast is pretty striking.” But he is more skeptical that this particular mechanism will turn out to be universal, cautioning that the process of aging is so chaotic and haphazard that the notion of a universal may not be useful.

Sinclair says the finding also provides a plausible explanation for two well-known phenomena: that DNA damage accelerates aging, and that patterns of gene expression tend to go awry as an animal gets older.

The sirtuins have received considerable attention in recent years for their apparent role in aging. An overabundance of sirtuins extends the life spans of yeast, nematodes, and flies. In addition, molecules that seem to activate sirtuins–such as resveratrol, found in red wine–have a protective effect against some age-related diseases in mice. Sinclair cofounded Sirtris Pharmaceuticals in Cambridge, MA, to investigate the therapeutic possibilities of highly potent resveratrol-like molecules. The company is testing a series of products, including a treatment for treating type 2 diabetes.

The new study adds to this growing body of evidence for the many ways sirtuins contribute to aging and age-related disease. “SIRT1 is reported to do so many different things now; the challenge is going to be figuring out which of those it really does, and which of those are really important for diseases,” says Brian Kennedy, another former member of Guarente’s lab. Kennedy, now an associate professor of biochemistry at the University of Washington, was not involved in the study.

Guarente also emphasizes the broad importance of sirtuins, beyond the newly discovered SIRT1 mechanism. “The universal in aging we already know is sirtuins; they do so many things,” he says. “The best way to approach this is to be able to trigger sirtuins so that you get all of the outputs and all of the benefits that they can bestow,” he adds, noting that many of those outputs are unrelated to the new mechanism.

Sinclair and his colleagues also found evidence of a link between the SIRT1 mechanism and cancer, a disease strongly associated with old age. When dosed with resveratrol or beefed up with an extra copy of the SIRT1 gene, mice normally prone to cancer developed fewer tumors. Both of these interventions increased the available amount of SIRT1, likely enhancing the protein’s ability to repair the DNA damage that leads to cancer without compromising its function as a gene regulator.

SIRT1 was already known to regulate a handful of mouse genes, but the new study revealed hundreds more. Many of these genes were found to be overexpressed in the brains of aging mice, underlining the potential importance of SIRT1-based gene deregulation in the aging process.

While the striking parallel between mice and yeast suggests that sirtuins’ competing dual roles may be relevant in a wide variety of organisms, it remains to be seen just how that mechanism fits into the larger picture of mammalian aging, says Vijg. Nonetheless, Sinclair is confident that his group has uncovered a potentially universal mechanism. “Life, in general, has an Achilles heel,” says Sinclair, “and this is it.”

Dr. Nathan Wolfe tracks zoonotic viruses, potentially deadly viruses, passed from animals to humans.

“What’s changed is, in the past you had smaller human populations; viruses would infect them and go extinct. Viruses actually need population density as fuel.”

NYABBISAN, Cameroon,CNN.COM, December 10, 2008, by Anderson Cooper —

The animals are gone.

Deep in a remote region of Cameroon, we are following two hunters looking for bush meat — forest animals they can kill to feed their families. They’ve spent hours in the forest already, but all the traps they’ve set are empty. They will have to push deeper into the forest and they may be hunting for days.

Last year, rising food prices touched off riots around the world, killing dozens of people. Unable to afford basic supplies, communities in Central Africa are increasingly turning to the forests for food. In doing so, hunters expose themselves to hidden dangers – microscopic pathogens living in the blood of forest animals.

Most of the viruses are harmless, but some are potentially deadly when passed to humans. Scientists point out there’s nothing new about these viruses. What is new is the frequency of people’s contact with them and how easily they can now be spread around the world.

World-renowned epidemiologist Dr. Nathan Wolfe is following the hunters.

“Individuals have been infected with these viruses forever,” Wolfe said. “What’s changed, though, is in the past you had smaller human populations; viruses would infect them and go extinct. Viruses actually need population density as fuel.”

Wolfe works mostly in the forests of Cameroon tracking these viruses that can jump from animals to humans – what are called zoonotic viruses.

The most prolific and deadly zoonotic is HIV, the virus that causes AIDS. In 1999, scientists at the University of Alabama at Birmingham traced the origins of HIV back to a subspecies of chimpanzee. Scientists think that the virus might have jumped to humans when the blood of an infected chimpanzee came in contact with the blood of a bush meat hunter during the killing or butchering of the animal.

It took decades, but that simple, seemingly insignificant transmission set off a global epidemic, or pandemic, that so far has killed or infected tens of millions of people. Scientists think HIV probably crossed into humans as far back as the early 1900s, but it wasn’t until air travel became common that the virus spread, and AIDS became a global epidemic in the 1980s.

“We’re now so profoundly interconnected that it will be the case things will enter into the human population and will spread globally,” said Wolfe.

The centerpiece of Wolfe’s work is trying to stop the next pandemic before it starts. He’s using a recent $11 million grant from Google and the Skoll Foundation to continue something called the Global Viral Forecasting Initiative or GVFI. It’s a kind of early-warning system to track the transmission of viruses in virus hot spots around the world. In addition to Cameroon, Wolfe has teams in the Democratic Republic of Congo, China, Malaysia, Madagascar and Laos.

Wolfe likens his work to the way an intelligence service tracks threats made by potential terrorists. His teams cross-reference the different viruses jumping over into humans – what he calls the viral chatter. By doing so, they can identify previously unknown viruses and perhaps stop them before they spread.

One zoonotic virus that Wolfe and his team are paying particularly close attention to is called monkeypox. It’s a virus that intermittently flares up in Central African countries; last year it killed more than 20 people in the Democratic Republic of the Congo.

The name monkeypox is a misnomer — scientists don’t think it comes from primates and think it’s more likely it comes from forest rodents. The virus manifests itself much like chickenpox, with sores that cover the body. Fatigue and body aches are common symptoms. But because doctors can’t be sure of its origins, treating — much less curing it — is difficult. Most of the patients are given general antibiotics and the virus is allowed to run its course.

It’s unlikely the current viral strain of monkeypox could become a pandemic, because it loses strength as it passes from person to person. But it spread to the United States in 2003 when some African rodents were imported as pets. Wolfe is most intrigued by monkeypox because its origins are unknown. In fact, monkeypox is one of the many viruses we know very little about.

“By documenting them, we’re potentially getting to a place where we can prevent pandemics instead of waiting for something like AIDS to happen and spread globally. To actually catch it earlier could potentially save millions of lives,” said Wolfe.

For hunters, like the two men the “Planet in Peril” crew has been following, viruses and science seem remote things to be concerned about. These men and an increasing number of people like them must hunt the forests simply to feed their families. But for the rest of us, with population and food pressures increasing and deadly zoonotic viruses lurking in the forest, what the hunters are doing now has the potential to impact us all.

Charlie Moore contributed to this report

Hunters facing food shortages in Central Africa push deep into forests for food, exposing themselves to viruses.

Coy contracted monkeypox through contact with bush meat. She’ll be quarantined for weeks — there’s no cure.