Medical Breakthroughs

Cedars-Sinai Heart Institute researchers have reprogrammed ordinary heart cells to become exact replicas of highly specialized pacemaker cells by injecting a single gene (Tbx18)-a major step forward in the decade-long search for a biological therapy to correct erratic and failing heartbeats.

The advance will be published in the Jan 8 issue of Nature Biotechnology and also will be available on the journal's website.
"Although we and others have created primitive biological pacemakers before, this study is the first to show that a single gene can direct the conversion of heart muscle cells to genuine pacemaker cells. The new cells generated electrical impulses spontaneously and were indistinguishable from native pacemaker cells," said Hee Cheol Cho, PhD., a Heart Institute research scientist.
Pacemaker cells generate electrical activity that spreads to other heart cells in an orderly pattern to create rhythmic muscle contractions. If these cells go awry, the heart pumps erratically at best; patients healthy enough to undergo surgery often look to an electronic pacemaker as the only option for survival.
The heartbeat originates in the sinoatrial node (SAN) of the heart's right upper chamber, where pacemaker cells are clustered. Of the heart's 10 billion cells, fewer than 10,000 are pacemaker cells, often referred to as SAN cells. Once reprogrammed by the Tbx18 gene, the newly created pacemaker cells -- "induced SAN cells" or iSAN cells -- had all key features of native pacemakers and maintained their SAN-like characteristics even after the effects of the Tbx18 gene had faded.
But the Cedars-Sinai researchers, employing a virus engineered to carry a single gene (Tbx18) that plays a key role in embryonic pacemaker cell development, directly reprogrammed heart muscle cells (cardiomyocytes) to specialized pacemaker cells. The new cells took on the distinctive features and function of native pacemaker cells, both in lab cell reprogramming and in guinea pig studies.
Previous efforts to generate new pacemaker cells resulted in heart muscle cells that could beat on their own. Still, the modified cells were closer to ordinary muscle cells than to pacemaker cells. Other approaches employed embryonic stem cells to derive pacemaker cells. But, the risk of contaminating cancerous cells is a persistent hurdle to realizing a therapeutic potential with the embryonic stem cell-based approach. The new work, with astonishing simplicity, creates pacemaker cells that closely resemble the native ones free from the risk of cancer.
For his work on biological pacemaker technology, Cho, the article's last author, recently won the Louis N. and Arnold M. Katz Basic Research Prize, a young investigator award of the American Heart Association.
"This is the culmination of 10 years of work in our laboratory to build a biological pacemaker as an alternative to electronic pacing devices," said Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute and Mark S. Siegel Family Professor, a pioneer in cardiac stem cell research. A clinical trial of Marbán's stem cell therapy for heart attack patients recently found the experimental treatment helped damaged hearts regrow healthy muscle.
If subsequent research confirms and supports findings of the pacemaker cell studies, the researchers said they believe therapy might be administered by injecting Tbx18 into a patient's heart or by creating pacemaker cells in the laboratory and transplanting them into the heart. But additional studies of safety and effectiveness must be conducted before human clinical trials could begin.

Using an artificial protein that stimulates the body's natural immune system to fight cancer, a research team at Duke Medicine has engineered a lethal weapon that kills brain tumors in mice while sparing other tissue. If it can be shown to work in humans, it would overcome a major obstacle that has hampered the effectiveness of immune-based therapies.

The protein is manufactured with two arms -- one that exclusively binds to tumor cells and another that snags the body's fighter T-cells, spurring an attack on the tumor. In six out of eight mice with brain tumors, the treatment resulted in cures, according to findings published Dec. 17, 2012, in the Proceedings of the National Academy of Sciences.
"This work represents a revival of a somewhat old concept that targeting cancer with tumor-specific antigens may well be the most effective way to treat cancer without toxicity," said senior author John H. Sampson, M.D., PhD, a neurosurgeon at The Preston Robert Tisch Brain Tumor Center at Duke. "But there have been problems with that approach, especially for brain tumors. Our therapeutic agent is exciting, because it acts like Velcro to bind T-cells to tumor cells and induces them to kill without any negative effects on surrounding normal tissues."
Sampson and colleagues focused on the immune approach in brain tumors, which are notoriously difficult to treat. Despite surgery, radiation and chemotherapy, glioblastomas are universally fatal, with a median survival of 15 months.
Immunotherapies, in which the body's B-cells and T-cells are triggered to attack tumors, have shown promise in treating brain and other cancers, but have been problematic in clinical use. Treatments have been difficult to administer at therapeutic doses, or have spurred side effects in which the immune system also attacks healthy tissue and organs.
Working to overcome those pitfalls, the Duke-led researchers designed a kind of connector -- an artificial protein called a bispecific T-cell engager, or BiTE -- that tethers the tumor to its killer. Their newly engineered protein includes fractions of two separate antibodies, one that recruits and engages the body's fighter T-cells and one that expressly homes in on an antigen known as EGFRvIII, which only occurs in cancers.
Once connected via the new bispecific antibody, the T-cells recognize the tumor as an invader, and mount an attack. Normal tissue, which does not carry the tumor antigen, is left unscathed.
"One of the major advantages is that this therapy can be given intravenously, crossing the blood-brain barrier," said lead author Bryan Choi, a dual M.D-PhD candidate at Duke. "When we gave the therapy systemically to the mice, it successfully localized to the tumors, treating even bulky and invasive tumors in the central nervous system."
The team also developed an antidote to other current immune-targeting therapies that have a toxic effect, enhancing their safety profiles and bolstering their effectiveness.
"Additional studies will concentrate on whether these findings can be replicated in human trials, and whether the treatment is affected by the use of current therapies such as radiation and chemotherapy," Sampson said.

Four thousands of years, our thirst for the legendary Fountain of Youth has been nearly as strong as our propensity for perpetuating the myth.

However, over the last 20 years, the fertile headwaters of molecular biology have been pumping out anything but folklore. Not only have these waters yielded a precipitous stretch in understanding the aging process, they’re potentially guiding us closer to the source of everlasting youth.

From this flow now comes word that biologists from the University of California, Berkeley have tapped an influential longevity gene that can reverse cell degeneration associated with aging. That’s right, they’re not just offering a sip from the fountain, they’re turning back the clock at the molecular level.

The new study, published in Cell Reports, represents a major discovery and offers new hope for development of targeted treatments for a long list of age-related degenerative diseases, such as heart disease, Alzheimer's and arthritis, just to name a few.
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The biologists, lead by UC Berkeley assistant professor of nutritional science and toxicology Danica Chen, focused their attention on one protein in particular: SIRT3. It’s one in a class of proteins called surtuins, long known to regulate aging.

Biologists found that SIRT3 plays a significant role in helping aged blood stem cells cope with the oxidative stress of the aging process. When the blood stem cells of aged mice were infused with SIRT3, it regenerated new blood cells, providing evidence of a reversal in the age-related degeneration of the cells’ function.

“This is really the first demonstration that sirtuins may be able to actually reverse aging-associated degeneration,” Chen told Discovery News.

“We known aging can be regulated so we may be able to manipulate the molecular pathways and slow down the process,” she added. “But there's never been a demonstration where we could reverse age. It’s really the next big step.”

Chen cited molecular biologist Cynthia Kenyon’s pioneering work in the early 1990s as perhaps the biggest breakthrough in understanding that aging is not a random, uncontrolled process, but rather a highly regulated development. In 1993, Kenyon published a study in Nature that showed a single gene mutation in a tiny worm (C. elegans) could double its lifespan, opening up the floodgates of intensive studies on age manipulation.

“We know there are a lot of techniques out there,” said Chen. “For example, you can use transgenic mouse models to upregulate sirtuins” to increase the quality of a cell “but those only address the question of whether you can slow aging. But you can’t really address the question of whether you could reverse aging.”

Unless, of course, you find the right key, which Chen and colleagues may have found in SIRT3.

“We’re particularly interested in SIRT3,” Chen said, “because we found that it’s highly enriched in hematopoietic stem cells.” These are blood stem cells, highly regarded for their ability to completely reconstitute the blood system, the underlying capability of a successful bone marrow transplant.
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Also of interest is the location of where SIRT3 is found – in the mitochondria, the cell compartment that helps control growth and death.

“What I liked so much about our study is that SIRT3 is mitochondrial,” said study co-author Dr. Katharine Brown. “It’s certainly not acting as a transcription factor, it’s effecting metabolism and other aspects of cell signaling, which is clearly very important in aging.” Brown conducted the research as a Ph.D. student in Chen's lab.

To gauge the effects of aging, researchers observed the blood system of young mice that had the SIRT3 gene disabled. At first, the absence of SIRT3 made no difference on the young mice.

“This study definitely took a few years,” said Brown. “It was kind of frustrating at the beginning because we weren’t seeing any differences between the wild mice and the SIRT3 knockout mice.”

But why no difference in the knockout mice, if SIRT3 is such a key component? In a typical display of youthful exuberance, the blood stem cells of the young mice were able function well enough to stave off oxidative stress, which many believe causes aging when our bodies metabolize oxygen.

“A young person is able to handle the oxygen – making sure that the oxygen is going to the right place,” Brown said. “As we age, our ability to appropriately handle the oxygen and its chemical process is not as good, and because of that, it starts wreaking havoc.”

Sure enough, as the mice aged, the SIRT3-deficient mice started slowing down, showing significantly fewer blood stem cells and a decreased ability to regenerate new blood cells.
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As we age, our normal antioxidative system struggles to take care of our cells. That’s when SIRT3 can provide a well-needed boost to our antioxidant system. Unfortunately, SIRT3 levels diminish with age, so eventually our system is engulfed in degeneration.

So researchers decided to see what happened when they boosted the SIRT3 levels in the blood stem cells of the aged mice.

“Our first inclination was that the reason the SIRT3 knockout mice’s blood cells were not doing so well was due to a build up of oxidative damage,” said Brown. “But the surprise was when I reintroduced a mutated form of SIRT3 to the aged knockout cells. It improved their function as well.”

In other words, their experiment rejuvenating the aged stem cells' regenerative potential.

“Aging is just an accumulation of damage,” said Chen. “If you think that way, then it’s probably not reversible, because cells are already damaged and no longer functional. But what we show here is that oxidative stress-induced damage, in fact, is reversible.”

While further studies will be needed to see if this SIRT3 boost can actually make people live longer, Chen asserts that there’s more to this field of study than just the thirst for everlasting youth.

“It’s not so much about expanding lifespan. More so, I think the most important goal is to prevent and ultimately treat age-related diseases,” she said. “The idea is that if we can prevent aging, we can prevent all the diseases that are associated with aging. That’s really the major goal.”

When it comes to age-related diseases, Brown says there’s one aspect about SIRT3 she particularly likes.
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“While it seems to be helping function, other researchers have found that it can also act as a tumor suppressor,” she said. “One of the problems that you have when you have a ‘molecular fountain of youth’ is you might be making a cell more useful, but then elsewhere you may be increasing the risk of cancer.”

Asked if this study takes us another step closer to this “molecular fountain of youth,” Brown hesitated with a pregnant pause before ultimately saying, “Yes.” Duly noted, however, was her reluctance about throwing around the phrase “molecular fountain of youth.”

“A lot of times people use phrases and a lot of times I feel like that’s an oversimplification because biology is incredibly complicated,” she said. “But I think that it is interesting because SIRT3 is a single molecule that can have a pretty dramatic effect. It is working at the molecular level.”

RedOranje wrote:Amazing how few of the people begging for a science section have showed up here or shared any of these stories.

Contact lens with built-in telescope could help people with blinding disease
By Meera Senthilingam, for CNN
Updated 12:57 PM ET, Tue March 17, 2015


(CNN)Lights, mirrors, action! Scientists are developing smart contact lenses embedded with miniscule mirrors that can magnify your vision by almost three times.

The 1.55mm-thick lenses incorporate a thin reflective telescope made of mirrors and filters; when light enters the eye it bounces off the series of mirrors and increases the perceived view of an object or person. It is hoped that the lens will improve the sight of people with age-related macular degeneration (AMD) -- the third leading cause of blindness globally.

AMD causes the loss of central vision due to gradual damage to the eye's retina and there are few options for cure or treatment. "AMD is the biggest problem where magnification is a proven visual aid," says Eric Tremblay, research scientist at EPFL in Switzerland.

Tremblay led the optical design of the lens, which is based on a surgically implantable telescope currently used by some patients with AMD, but which is more invasive than a lens. "With a contact lens, it's easy to try it," says Tremblay.

Making the switch

A key innovation with the lenses is the added ability to switch between magnified and regular vision through a complementary pair of glasses. The battery-powered glasses use LCD technology to watch the movement of the eye and a simple wink can alter their polarization and determine whether light entering is magnified or not. "Having the ability to switch on demand is attractive," says Tremblay.

The ability to selectively magnify your vision makes the design of the glass-lens combination more suitable for daily life. "When magnified you lose a lot of your field of view, your peripheral vision," says Tremblay. A strategic wink will enable users to keep an eye on their periphery, such as cars approaching them as they cross a street, whilst also being able to zoom in and recognize the faces of those around them.

The team developed their technology on scleral lenses, which have an increased thickness and diameter, making them commonly used for more special purpose eye care. "[They provide] a lot more area to work with," says Tremblay. The challenge these lenses bring with them, however, is comfort, as they impede the amount of oxygen reaching the eye.

The most recent prototype, unveiled by the team in February, overcame this challenge by introducing air channels to aid the flow of oxygen to the eye. But the team hopes to improve this further still by instead developing a contact lens solution saturated with oxygen which can be stored and slowly released into the eye. "[We will] build reservoirs into the back of the lens," says Tremblay.

The lenses have only been trialled on a handful of humans to test for comfort, with the majority of research to date performed in the lab using a model chemical eye. But more human trials are on the cards with the eventual goal of daily wearable contacts to aid the visually impaired.

"We want it to move in the direction of a real world vision aid," says Tremblay.

Getting smarter

These are not the first smart contact lenses. Other prototypes have been developed to monitor, as well as improve, health in both the eye and across the body.

Alcon, the eye care division of Novartis, formed a partnership with Google X in 2014 to develop smart-lens technologies for a range of medical eye care applications. One of the first examples of using lenses in this form was Sensimed, a spin-off also emerging from EPFL. Sensimed's Triggerfish technology monitors the progression of glaucoma -- the second leading cause of blindness, affecting more than 4.5 million people globally.

Glaucoma is a progressive cause of blindness caused by deterioration of the eye's optic nerve. The traditional test used by optometrists to monitor patients uses puffs of air to measure pressure in the eye but such measurements are not ideal.

"The big need in glaucoma is for a 24-hour picture of what's happening inside the eye," says David Bailey, CEO of Sensimed. Its smart lens uses strain gauges and sensors embedded inside a chip located in the lens to measure changes in the volume of liquid in the eye as a surrogate measurement of pressure. It can be worn over a 24-hour period to monitor pressure patterns and communicate data wirelessly to a recording device worn around the user's neck.

Optomotrist James Wolffsohn, spokesperson for the British Contact Lens Association, looks forward to one day using technologies like the telescopic lens in clinical practice. "The lens seems an interesting concept to provide optical magnification to the retina when required," he says. But he adds that there will be challenges in reaching that stage: "It is currently a scleral lens and thick, including rigid mirror elements which are likely to affect corneal physiology and comfort." Wolffsohn has seen colleagues trial the more established Triggerfish technology to monitor glaucoma and is optimistic about the future of the field. "There are also many other exciting developments in innovative uses of contact lenses," he says.

"The eye is the window to many disease states," says Bailey, who believes contact lenses are the future for eye care, both in terms of clinical use and lifestyle management. More than 30 million people wear contact lenses in the United States alone, according to the Centers for Disease Control, which means they could be a non-invasive path to health management -- be it blindness progression or even insulin or alcohol level monitoring.

"Eye-sensing on contact lenses is here to stay ... in one form or another," says Bailey.

Gene therapy: 'Tame HIV' used to cure disease
By James Gallagher Health editor, BBC News website 8 hours ago


The lives of six boys with a deadly genetic disease have been transformed by a pioneering treatment to correct errors in their DNA, say doctors.

A defective immune system in Wiskott-Aldrich syndrome leaves people vulnerable to infections and bleeding.

A British and French study, published in JAMA, used tamed HIV to correct the defects.

One child who needed a wheelchair can now move freely, while symptoms have improved in the other patients.

The syndrome affects up to 10 children in every million born and almost exclusively affects boys.

Even tiny bumps and scrapes can lead to wounds that are slow to close in patients. Eczema is common, they face repeat infections including pneumonia as well as some cancers and autoimmune diseases.

It all stems from an error in the genetic code that contains the building instructions for a key element in the immune system - a protein called WAS.


Therapy

The main treatment is a bone marrow transplant - but that is an option only when the donor is a close tissue match, such as a sibling.

The trial at Great Ormond Street Hospital, in London, and Necker Children's Hospital, in France, removed part of the children's bone marrow.

It was purified in the laboratory to find the cells that regenerate the immune system and a tamed version of HIV was used to "infect" the cells with the correct DNA.

The corrected bone marrow cells were then put back into the children.

In six out of seven boys, the therapy was a success. It reversed symptoms and massively cut the number of nights spent in hospital. One French child with severe autoimmune disease no longer needs a wheelchair.

Another died from a drug-resistant herpes infection acquired before the therapy started.