Silicon retina mimics biology for a clearer view

20 October 2006
NewScientist.com news service
Tom Simonite

A silicon chip that faithfully mimics the neural circuitry of a real retina could lead to better bionic eyes for those with vision loss, researchers claim.

About 700,000 people in the developed world are diagnosed with age-related macular degeneration each year, and 1.5 million people worldwide suffer from a disease called retinitis pigmentosa. In both of these diseases, retinal cells, which convert light into nerve impulses at the back of the eye, gradually die.

Most artificial retinas connect an external camera to an implant behind the eye via a computer (see 'Bionic' eye may help reverse blindness). The new silicon chip created by Kareem Zaghloul at the University of Pennsylvania, US, and colleague Kwabena Boahen at Stanford University, also in the US, could remove the need for a camera and external computer altogether.

The circuit was built with the mammalian retina as its blueprint. The chip contains light sensors and circuitry that functions in much the same way as nerves in a real retina – they automatically filter the mass of visual data collected by the eye to leave only what the brain uses to build a picture of the world.
Fully implanted

"It has potential as a neuroprosthetic that can be fully implanted," Zaghloul told New Scientist. The chip could be embedded directly into the eye and connected to the nerves that carry signals to the brain's visual cortex.

To make the chip, the team first created a model of how light-sensitive neurons and other nerve cells in the retina connect to process light. They made a silicon version using manufacturing techniques already employed in the computer chip industry.

Their chip measures 3.5 x 3.3 millimetres and contains 5760 silicon phototransistors, which take the place of light-sensitive neurons in a living retina. These are connected up to 3600 transistors, which mimic the nerve cells that process light information and pass it on to the brain for higher processing. There are 13 different types of transistor, each with slightly different performance, mimicking different types of actual nerve cells.

"It does a good job with some of the functions a real retina performs," says Zaghloul. For example, the retina chip is able to automatically adjust to variations in light intensity and contrast. More impressively, says Patrick Deganeer, a neurobionics expert at Imperial College London, UK, it also deals with movement in the same way as a living retina.
Changing scene

The mammalian brain only receives new information from the eyes when something in a scene changes. This cuts down on the volume of information sent to the brain but is enough for it to work out what is happening in the world.

The retina chip performs in the same way. The lowest image (right) shows how this allows it to extract useful data from a moving face.

As well as having the potential to help humans with damaged vision, future versions of the retina chip could help robots too, adds Deganeer. "If you can perform more processing in hardware at the front end you reduce demand on your main processor, and could cut power consumption a lot," he explains.

Zaghloul and Boahen are currently concentrating on reducing the size and power consumption of the retina chip before considering clinical trials.

Journal reference: Journal of Neural Engineering (vol 3, p 257)

MIT material stops bleeding in seconds

Work could significantly impact medicine

CAMBRIDGE, Mass.--MIT and Hong Kong University researchers have shown that some simple biodegradable liquids can stop bleeding in wounded rodents within seconds, a development that could significantly impact medicine.
When the liquid, composed of protein fragments called peptides, is applied to open wounds, the peptides self-assemble into a nanoscale protective barrier gel that seals the wound and halts bleeding. Once the injury heals, the nontoxic gel is broken down into molecules that cells can use as building blocks for tissue repair.
"We have found a way to stop bleeding, in less than 15 seconds, that could revolutionize bleeding control," said Rutledge Ellis-Behnke, research scientist in the MIT Department of Brain and Cognitive Sciences.
This study will appear in the online edition of the journal Nanomedicine on Oct. 10 at http://www.nanomedjournal.com/inpress. It marks the first time that nanotechnology has been used to achieve complete hemostasis, the process of halting bleeding from a damaged blood vessel.
Doctors currently have few effective methods to stop bleeding without causing other damage. More than 57 million Americans undergo nonelective surgery each year, and as much as 50 percent of surgical time is spent working to control bleeding. Current tools used to stop bleeding include clamps, pressure, cauterization, vasoconstriction and sponges.
In their experiments on hamsters and rats, the MIT and HKU researchers applied the clear liquid containing short peptides to open wounds in several different types of tissue - brain, liver, skin, spinal cord and intestine.
"In almost every one of the cases, we were able to immediately stop the bleeding," said Ellis-Behnke, the lead author of the study.
Earlier this year, the same researchers reported that a similar liquid was able to partially restore sight in hamsters that had had their visual tract severed. In that case, the self-assembling peptides served as an internal matrix on which brain cells could regrow.
While experimenting with the liquid during brain surgery, the researchers discovered that some of the peptides could also stop bleeding, Ellis-Behnke said. He foresees that the material could be of great use during surgery, especially surgery that is done in a messy environment such as a battlefield. A fast and reliable way to stop bleeding during surgery would allow surgeons better access and better visibility during the operation.
"The time to perform an operation could potentially be reduced by up to 50 percent," said Ellis-Behnke.
Unlike some methods now used for hemostasis, the new materials can be used in a wet environment. And unlike some other agents, it does not induce an immune response in the animals being treated.
When the solution containing the peptides is applied to bleeding wounds, the peptides self-assemble into a gel that essentially seals over the wound, without harming the nearby cells. Even after excess gel is removed, the wound remains sealed. The gel eventually breaks down into amino acids, the building blocks for proteins, which can be used by surrounding cells.
The exact mechanism of the solutions' action is still unknown, but the researchers believe the peptides interact with the extracellular matrix surrounding the cells. "It is a completely new way to stop bleeding; whether it produces a physical barrier is unclear at this time," Ellis-Behnke said.
The researchers are confident, however, that the material does not work by inducing blood clotting. Clotting generally takes at least 90 seconds to start, and the researchers found no platelet aggregation, a telltale sign of clotting.
Other MIT researchers who are co-authors on the paper are Gerald Schneider, professor of brain and cognitive sciences, and Shuguang Zhang, associate director of MIT's Center for Biomedical Engineering. Collaborators at the University of Hong Kong Li Ka Shing Faculty of Medicine, Department of Anatomy, include Yu-Xiang Liang, David Tay, Wutian Wu, Phillis Kau and Kwok-Fai So, an MIT alumnus.

Rescuing injured hearts by enhancing regeneration

Animal study suggests novel way to reverse heart-attack damage

Using a two-drug approach, researchers at Children's Hospital Boston have demonstrated that it may be possible to rescue heart function after a heart attack and protect the heart from scarring. Working with rats, they combined an agent that overcomes a natural inhibitor of cell division with a naturally occurring growth factor that encourages blood vessel growth (angiogenesis). Together, these two agents enabled heart-muscle cells to multiply and the heart to regain its function after a simulated myocardial infarction. The study will appear in the October 17 issue of the Proceedings of the National Academy of Sciences (posted online during the week of October 9).
Normally, after a heart attack, the damaged heart muscle cannot grow back and is instead replaced by scar tissue. Excessive scarring can impair the heart's pumping capacity and can lead to life-threatening arrhythmias. Heart-muscle cells (cardiomyocytes) normally cannot replicate in mammals, a major obstacle to regeneration. However, in a paper last year, Felix Engel, PhD, and Mark Keating, MD, in the Department of Cardiology at Children's Hospital Boston, showed that they could coax cardiomyocytes to multiply in a petri dish by inhibiting an enzyme known as p38 MAP kinase, which normally suppresses cardiomyocyte replication. [See: here]
Engel and Keating (Keating is now at the Novartis Institute for BioMedical Research) now build on this finding. They studied 120 rats, some with simulated heart attacks. After the injury, the animals were randomly assigned to receive injections with a p38 MAP kinase inhibitor alone, the angiogenesis stimulator FGF1 alone, both agents together, or saline (placebo) for four weeks. Three months later, rats that had received both FGF1 and the p38 MAP kinase inhibitor had markedly improved heart function, as measured on echocardiograms: their hearts pumped almost as well as the hearts of uninjured rats. They also had reduced thinning of the cardiac wall and the least amount of scarring.
Rats receiving only the p38 MAP kinase inhibitor had increased proliferation of cardiomyocytes, but no longer had improved heart function at three months. Those receiving only FGF1 maintained their functional improvement, but did not show as much cell proliferation as those receiving the p38 MAP kinase inhibitor. Rats receiving both agents had the greatest improvements in both cell proliferation and heart function.
The findings suggest that getting cardiomyocytes to replicate is not enough to rescue heart function, but that angiogenesis is also needed, Engel says.
"Regeneration is not just making more cardiomyocytes," he says. "Cardiomyocytes need a blood supply and oxygen to survive. FGF1 did not have a great effect on cell proliferation, but we found it was providing a new blood supply. If you just inhibit p38 MAP kinase, you don't get blood vessels."
Two important steps are needed to turn these findings into a treatment, Engel says. First is to show that the treatment works when not given immediately after the heart attack, since many people sustain progressive damage to their hearts from repeated minor infarctions. In this study, rats were treated soon after injury.
Second is the need to develop a safe delivery method. Because FGF1 stimulates angiogenesis, it has the potential for serious side effects if it goes to places other than the heart, possibly promoting tumor growth, for example. And the p38 MAP kinase inhibitor has been shown to damage the liver.
"Every treatment trying to induce proliferation of cardiomyocytes also carries a risk of inducing tumor growth, and thus you have to limit the time and location of treatment," Engel adds.
One possibility is to inject smaller doses of the agents into the damaged area of the heart in gel form, or instill them through a catheter, so that they would remain in the heart and be released slowly over time. Engel and colleagues recently reported another compound that stimulates cardiomyocyte proliferation (Chemistry and Biology, Sept. 2006), and others are under investigation.
"In the end, we'd like a treatment that could be given systemically," Engel says.

Blood cells linked to heart attacks, other inflammatory diseases

Cox-2 production initiated by cellular cross talk

SALT LAKE CITY -- It's a case of miscommunication with catastrophic consequences.

Two human blood cells that help fight blood loss, infection, and inflammation are responsible as well for starting a series of molecular events that results in overproduction of Cox-2, an enzyme involved in heart attack, stroke, atherosclerosis, and other inflammatory diseases.

The finding by researchers at the University of Utah and University of South Carolina means scientists may be able to develop drugs to prevent or lessen the severity of inflammatory diseases, such as atherosclerosis and heart attack. Discovery of the signaling mechanism will be invaluable in sorting out the roles Cox-2 plays in those diseases, according to Guy A. Zimmerman, M.D., University of Utah School of Medicine professor of internal medicine, senior author of the study detailing the research.

"This discovery has immediate clinical relevance," said Zimmerman, director of the medical school's Program in Human Molecular Biology and Genetics. "This opens the potential of developing medications for both the prevention of long-term atherosclerosis (clogged arteries) and the acute events of heart attack."

The study, reported in the Journal of Clinical Investigation online, also was led by Dan A. Dixon, a former member of Zimmerman's lab now at South Carolina.

The researchers identified a biochemical signaling pathway between human blood platelets, cells essential for blood clotting, and monocytes, white blood cells the body makes to fight inflammation and infection. But, according to Zimmerman, the biological systems involved in blood clotting and inflammation also are related to a host of human diseases.

The Utah and South Carolina researchers discovered that the blood platelet signals the monocyte two times, triggering production of Cox-2, an enzyme that helps regulate inflammation. But when blood platelets and monocytes get their signals crossed, it can lead to overproduction of the enzyme and result in cardiovascular diseases that strike and kill millions of people worldwide.

Zimmerman compares the signaling between blood platelets and monocytes to a pair of molecular control switches that turn Cox-2 production on and off. "It's a mechanism for precise control of Cox-2 production," he said. "But if one of the switches is turned on too high or low, it can lead to inappropriate production of Cox-2 in disease."

The first signal from the platelet tells the monocyte to turn on the gene that provides the instructions necessary to make Cox-2. These instructions are carried in small molecule called messenger RNA. When the blood platelet signals the monocyte, the cell decodes the instructions from the Cox-2 gene in a process called transcription. This results in production of messenger RNA that specifically codes for Cox-2. After the messenger RNA is transcribed, the blood platelet then sends a second signal to the monocyte that regulates stability of the Cox-2 messenger RNA and further decoding of the genetic information in a process called translation.

This results in production of the Cox-2 protein and controls how much, and at what time point, it is produced.

Drugs called non-steroidal anti-inflammatory agents, which inhibit production of Cox-2 and reduce inflammation, are some of the most widely used medications in the world for arthritis and other inflammatory diseases. But some of these drugs, also called Cox-2 inhibitors, such as Vioxx, increase the chance of heart attack.

Identifying the signaling mechanism between blood platelets and monocytes makes it possible to develop new drugs to modify Cox-2 production. "Knowing these steps gives you an initial blueprint about how to modify Cox-2," Zimmerman said. Understanding this mechanism may enable researchers to develop drugs that help people during a heart attack, or prevent heart attack, stroke or other inflammatory diseases.

AGE Crosslink breaker

Alagebrium is the only A.G.E. Crosslink Breaker in advanced human testing. The compound has demonstrated promising results in several Phase 2 human clinical trials and is being developed initially for cardiovascular and vascular diseases. Results to date suggest that alagebrium may be a novel therapy for a number of conditions that occur as a result of myocardial or vascular alterations associated with aging or diabetes. Preliminary evidence suggests that the compound is able to modify both the structure and function of the left ventricle (main pumping chamber of the heart) consistent with a partial reversal of pathology. Similarly, alagebrium has been shown to improve the reactivity and function of the arterial system. In addition, in all clinical testing to date, the compound has demonstrated a clean safety profile.

Archon X PRIZE for Genomics

On October 4, 2006, the X PRIZE Foundation announced the launch of its second prize — the Archon X PRIZE for Genomics. The $10 million cash prize has been created to revolutionize the medical world. The launch was attended by visionaries and entrepreneurs from around the globe who recognize the significance and impact that the Archon X PRIZE for Genomics will have on the fields of medicine and research.

Cloned mice created from fully differentiated cells, a milestone in cloning research

New research dismisses the notion that adult stem cells are necessary for successful animal cloning, proving instead that cells that have completely evolved to a specific type not only can be used for cloning purposes, but they may be a better and more efficient starting point. As proof, researchers report they created two mouse pups from a type of blood cell that itself is incapable of dividing to produce a second generation of its own kind.
This is the first demonstration that an animal can be derived directly from a fully differentiated cell, report lead researchers Xiangzhong (Jerry) Yang, Ph.D., of the University of Connecticut, and Tao Cheng, M.D., of the University of Pittsburgh, in the journal Nature Genetics.

Moreover, they say results of their studies provide compelling evidence that Dolly the sheep and other mammals cloned by somatic cell nuclear transfer were most likely derived from fully differentiated cells, not adult stem cells, as most have argued in the nine years since Dolly was first created. Because stem cells have the ability to self-renew and differentiate into any specialized cell type, they have been heralded for their promise for treating a variety of diseases and conditions. Yet, even for cloning of an embryo to the blastocyst stage, from which embryonic stem cells can be generated, adult stem cells have yielded disappointing results, with success rates in the range of 1 to 5 percent.

Somatic cell nuclear transfer (SCNT), the scientific term for cloning, involves creating an embryo by using a nucleus that's been removed from a somatic cell – any cell other than a reproductive cell – and transferring it into an unfertilized egg that has had its chromosomes removed. Because the resulting new embryo contains the entire genome of the donor somatic cell it is an identical copy. This cloned embryo is then implanted into a surrogate mother, and, if the process is successful, is carried to term.

In their studies, the researchers compared the efficiency for cloning mice using a fully differentiated blood cell called a granulocyte with its ancestor cells at different stages: hematopoietic stem cells, which are found in bone marrow and give rise to all red and white blood cells, and progenitor cells. Granulocytes are well characterized white blood cells unique for their segmented nuclei and the numerous granules in the cells' cytoplasm.

Surprisingly, the granulocytes were the most efficient donor cells for nuclear transfer among the different lineage cells, with 35 to 39 percent becoming a blastocyst, an early embryo consisting of about 100 to 150 cells, compared to 11 percent for the progenitor cells and only 4 percent for the stem cells. Only the granulocytes were able to produce two live cloned pups, although both died within a few hours of birth. As a control, the researchers performed nuclear transfer using embryonic stem cells; 49 percent developed to the blastocyst stage and 18 cloned pups were born.

"Our results clearly demonstrate that there is no apparent advantage in using either adult stem cells or progenitor cells over fully differentiated cells as nuclear donors. To the contrary, we found that cloned pups can be produced from adult, fully differentiated somatic cells, a conclusion that goes against popular opinion and current hypotheses," says Dr. Yang, animal science professor, director of the University of Connecticut's Center for Regenerative Biology and co-corresponding author of the study.

"Even we were surprised to find fully differentiated cells were more efficient for cloning, because granulocytes are not capable of dividing. In fact, we repeated our experiments six times just to be sure. Now we can say with near certainty that a fully differentiated cell such as a granulocyte retains the genetic capacity for becoming like a seed that can give rise to all cell types necessary for the development of an entire organism," adds co-corresponding author Dr. Cheng, associate professor of radiation oncology at the University of Pittsburgh School of Medicine and director of stem cell biology and co-leader of the cancer stem cell program at the University of Pittsburgh Cancer Institute.

Previous attempts by scientists to produce animal clones directly from fully differentiated B cells, T cells and neurons had failed beyond the blastocyst stage. Only with a second step that involved combining the blastocyst with a fertilized embryo, which produces what biologists call a chimera, or by performing another nuclear transfer using the embryonic stem cells derived from these blastocysts, could "cloned" pups be produced. Even so, other researchers have countered these are not bona fide clones because they possess chromosomes that are not identical to those of the original donor nucleus.

Since Dolly, animal cloning using adult cells has been accomplished in more than a dozen mammalian species, but the process is highly inefficient. Even if the reconstructed eggs survive to the blastocyst stage, only a handful, at most, of these result in live young when implanted into a female.

Many have attributed cloning's limited success to a theory that clones must be derived from adult stem cells, which reside in a specific area of each tissue and remain quiescent until they are activated by the presence of disease or tissue injury. Yet, if this were true, Drs. Yang and Cheng point out, the results of their studies would have found the adult stem cells to be more efficient than the other, more differentiated cells.

"Of the 1,828 nuclear transfers we performed with stem cells, very few could develop to the blastocyst stage and not one clone was produced. With such odds, it's hard to believe that Dolly and other cloned animals could have possibly been derived from adult stem cells. Much more likely is that these animals were derived from fully differentiated tissue cells," Dr. Yang argues.

While more research is needed to determine if what they found with hematopoietic cells will be true for cells of other tissue types, the investigators say their current studies may have important implications for regenerative medicine, since the findings suggest the potential of adult stem cells in this arena may be more limited than previously thought. However, of particular interest to Dr. Cheng is the relevance of their findings to cancer stem cell research.

"An interesting question to me is whether SCNT can play a role in understanding or even reprogramming the behavior of cancer stem cells. Such studies may potentially reveal a new set of molecular targets that could aid in the treatment of cancer," says Dr. Cheng.

Source: University of Pittsburgh

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