Lab on a chip

Finding out whether that unusual sore in your mouth is cancerous should become a lot faster and easier in the years ahead following news that scientists have engineered the first fully automated, all-in-one test, or lab on a chip, that can be programmed to probe cells brushed from the mouth for a common sign of oral cancer.

About half the size of a toaster, the portable device yields results in just under 10 minutes. Currently, patients must undergo an often painful tissue biopsy and usually wait three days to a week for the lab results.

John McDevitt, PhD, a scientist at the University of Texas at Austin, US and the senior author on the paper, said his group’s proof of principle study showed that their test could accurately measure levels of epidermal growth factor receptor, or EGFR, on three distinct types of oral cancer cells. This protein, which is normally displayed on the surface of our cells, tends to be overproduced in oral tumour cells and serves as a measurable marker of oral cancer.

His group's next step is to program the device to read not just EGFR levels but those of other proteins and genes that, when altered, are indicative of a developing oral tumour. This work is well under way.

Regenerating tissue

University of Delaware (UD) scientists in the US have invented a novel biomaterial with surprising antibacterial properties that can be injected as a low-viscosity gel into a wound where it rigidifies on contact – opening the door to the possibility of delivering a targeted payload of cells and antibiotics to repair damaged tissue.

Regenerating healthy tissue in a cancer-ridden liver, healing a biopsy site and providing wounded soldiers in battle with pain-killing, infection- fighting medical treatment are among the myriad uses the scientists foresee for the new technology.

The patented invention by Joel Schneider, UD associate professor of chemistry and biochemistry, and Darrin Pochan, associate professor of materials science, and their research groups, marks a major step forward in the development of hydrogels for medical applications.

Formulating hydrogels as delivery vehicles for cells extends the uses of these biopolymers far beyond soft-contact lenses into an intriguing realm once viewed as the domain of science fiction, including growing bones and organs to replace those that are diseased or injured.

“This is an area that will be exploding over the next decade,” Pochan predicts.

Hydrogels are formed from networks of super-absorbent, chain-like polymers. Although they are not soluble in water, they soak up large amounts of it, and their porous structure allows nutrients and cell wastes to pass right through them.

Schneider and Pochan and their research teams have been focusing on developing peptide-based hydrogels that, once implanted in the human body, will become scaffolds for cells to hold onto and grow – cells such as fibroblasts, which form connective tissue, and osteoblasts, which form bone.

UD's peptide-based hydrogels display several novel features. Not only are they cytocompatible, meaning that they are not toxic to the living cells they are enlisted to deliver, but some of the gels are inherently antimicrobial, killing certain gram-negative and grampositive bacteria, a characteristic the research team currently is exploring.

The UD hydrogels also can be freeze-dried into a powder and reconstituted into a solution for use. They can be injected from a syringe, offering a minimally invasive approach to medical treatment, as well as a targeted, “leak-proof' way of potentially delivering cells and drugs to a wound or diseased organ.

Understanding anaesthetics

An important clue to how anaesthetics work on the human body has been provided by the discovery of a molecular feature common to both the human brain and the great pond snail nervous system, scientists say. Researchers hope that the discovery of what makes a particular protein in the brain sensitive to anaesthetics could lead to the development of new anaesthetics with fewer side effects.

The study focuses on a particular protein found in neurons in the brain, known as a potassium channel, which stabilises and regulates the voltage across the membrane of the neuron. Communication between the millions of neurons in the brain – which is the basis of human consciousness and perception, including perception of pain – involves neurons sending nerve impulses to other neurons. In order for this to happen, the stabilising action of the potassium channel has to be overcome. Earlier studies on great pond snails by the same team identified that anaesthetics seemed to selectively enhance the regulating action of the potassium channel, preventing the neuron from firing at all – meaning the neuron was effectively anaesthetised.

The new research has identified a specific amino acid in the potassium channel which, when mutated, blocks anaesthetic activation. Lead author, biophysics professor Nick Franks from Imperial College London, explains how this will allow the importance of the potassium channel in anaesthetic action to be established:

“We’ve known for over 20 years now that these potassium channels in the human brain may be important anaesthetic targets. However, until now, we’ve had no direct way to test this idea. Because a single mutation can block the effects of anaesthetics on this potassium channel without affecting it in any other way, it could be introduced into mice to see if they also become insensitive to anaesthetics. If they do, then this establishes the channel as a key target.”

The research is published in the 20 July issue of the Journal of Biological Chemistry.

Asthma crystals

Researchers at Karolinska Institutet in Sweden have managed to elucidate the crystal structure of a human membrane protein – LTC4 synthase – which has a major influence on the development of asthma. LTC4 synthase is extremely difficult to analyse, and previously only low resolution information has been available on two membrane protein structures. The scientists now believe that their work will enable the development of new and better therapeutics against inflammations in the pulmonary tract.

Asthma attacks are caused by an acute inflammatory reaction in the airways, a reaction that is largely due to actions of LTC4 synthase. For this reason asthma medicines often aim at blocking the downstream effects of LTC4 synthase. However, there is a need for new pharmaceutical alternatives, since not all patients respond to the existing medicines.

The new results are also very important as they can lead the way for the development of new and more effective therapeutics against other diseases. Some 40% of the proteins of interest for pharmaceutical developments are membrane proteins. Until now detailed structural information on these proteins has been absent, and therefore it has been difficult to fully understand their function. The study is likely to lead the way for the determination of structures of other human membrane proteins. The elucidation of more membrane protein structures will help us understand fundamental processes that take place in the cell membranes.

Chronic pain

Scientists studying one of nature’s simplest organisms have helped to unravel the structure of a key molecule that controls pain in humans.

The findings – published in Nature – could rapidly advance research into the next generation of painkillers for relief of chronic conditions such as migraine and backache.

Chronic pain, unlike the acute pain associated with trauma, has no apparent physiological benefit, often being referred to as the ‘disease of pain’.

Complete and lasting relief of chronic pain is rare and often the clinical goal is pain management through one or more medications.

But now researchers at The University of Manchester, United Kingdom, have examined microscopic amoeboid organisms commonly called slime moulds in a bid to gain greater insight into these pain molecules, known as ‘P2X receptors’.

“In humans, P2X receptors look identical to one another and so scientists have had difficulty understanding how they function,” said Dr Chris Thompson, who carried out the research with Professor Alan North and Dr Sam Fountain in the Faculty of Life Sciences.

“By looking at slime mould we were effectively able to turn the evolutionary clock back a billion years to see how a more primitive P2X molecule functions.”

The team discovered that there was only a 10% similarity between human P2X and the slime mould equivalent. They were therefore able to deduce from evolutionary theory that it was these similar parts of the molecule that probably regulate pain in humans.

“It’s a big step forward in understanding how the molecule works and should make it possible to develop drugs that block the receptors’ actions,” said Dr Thompson.

“Inhibiting P2X as a potential pain-relief therapy would be the Holy Grail of rational drug design and could revolutionise the way we manage chronic pain conditions like back pain and migraine.”

Soft drinks

Middle-aged adults who drank more than one soft drink daily, either diet or regular, have a more than 40% greater rate of either having or developing metabolic syndrome., according to new data from the US National Heart, Lung, and Blood Institute (NHLBI).

Metabolic syndrome is a cluster of conditions that increase the risk for heart disease and a person is considered to have it if he or she has three or more of the following five risk factors: waist circumference greater than or equal to 89cm (women) or 101cm (men), fasting blood glucose of greater than or equal to 100 mg/dL, triglycerides greater than or equal to 150 mg/dL; blood pressure greater than or equal to 135/85 mmHg, and HDL “good” cholesterol below 40mg/dL for men or below 50 mg/dL for women.

Results from the Framingham Heart Study's “Soft Drink Consumption and Risk of Developing Cardio-Metabolic Risk Factors and the Metabolic Syndrome in Middle Aged Adults in the Community,” are published online in Circulation.

“Other studies have shown that the extra calories and sugar in soft drinks contribute to weight gain, and therefore heart disease risk,” said Elizabeth G Nabel, MD, director, NHLBI. “This study echoes those findings by extending the link to all soft drinks and the metabolic syndrome.”

Geckel adhesive

Scientists report they have merged two of nature's most elegant strategies for wet and dry adhesion to produce a synthetic material that one day could lead to more durable and longer-lasting bandages, patches, and surgical materials. As published in a recent issue of Nature, the scientists have designed a synthetic material that starts with the dry adhesive properties of the gecko lizard and supplements it with the underwater adhesive properties of a mussel.

The hybrid material, which they call a geckel nanoadhesive, proved in initial testing to be adherent under dry and wet conditions. It also adhered much longer under both extremes than previous gecko-based synthetic adhesives, a major issue in this area of research.

“Our work represents a proof of principle that it can be done,” said Phillip Messersmith, DDS, PhD, a scientist at Northwestern University in Evanston, Illinois, US, and the senior author on the paper. “A great deal of research still must be done to refine the fabrication process and greatly reduce its cost.”

According to the authors, their findings mark the first time that two polar opposite adhesion strategies in nature have been merged into a man-made reversible adhesive.

Messersmith envisions great possibilities for geckel. “Band aids already adhere well, except if you go swimming, take a shower, or somehow expose it to a lot of water,” said Messersmith. “So I think the most important thing with this adhesive is the added value of resisting immersion in water.

“I should add that the essential component of the wet adhesive polymer contains a chemical that we have discovered last year adheres well to mucosal surfaces, such as those inside our mouth,” he noted. “It may be possible to develop patches in the future that can be applied on the inside of the cheek to cover damaged tissue.”

SARS antibodies

An international team of investigators has identified the first human antibodies that can neutralise different strains of the virus responsible for outbreaks of severe acute respiratory syndrome (SARS). The researchers used a mouse model and in vitro assays (lab tests) to test the neutralising activity of the antibodies.

The research findings appear in the 2 July 2007, early online edition of the Proceedings of the National Academy of Sciences.

SARS outbreaks occurred in humans in 2002-2003 and again in 2003-2004, and each outbreak was thought to have occurred when the virus jumped from an animal host to humans. Therefore, it appears that animal strains of the virus may be capable of triggering a future human outbreak.

The research team was led by Dimiter S Dimitrov, PhD, head of the Protein Interaction Group at The US National Cancer Institute's Frederick, Maryland, campus.

Kanta Subbarao, MD, US National Institute of Allergy and Infectious Diseases, whose laboratory verified the efficacy of the anti-SARS antibodies in animal models, said: “What we need to prove for any vaccine, therapeutic, antibody, or drug is that it is effective not only against the strain of SARS virus isolated from people, but also against a variety of animal strains, because animals will be a likely source for re-emergence of the SARS virus.”

Dimitrov and his colleagues identified two human antibodies that bind to a region on the SARS virus’ spike glycoprotein that is called the receptor binding domain (RBD). One of the antibodies, called S230.15, was found in the blood of a patient who had been infected with SARS and later recovered. The second antibody, m396, was taken from a library of human antibodies the researchers developed from the blood of 10 healthy volunteers. Because humans already have immune cells that express antibodies that are very close to those that can effectively neutralise the SARS virus, m396 could be fished out from healthy volunteers. Dimitrov's team next determined the structure of m396 and its complex with the SARS RBD and showed that the antibody binds to the region on the RBD that allows the virus to attach to host cells.

If the antibodies were successful in binding to the SARS RBD, they would prevent the virus from attaching to the SARS coronavirus receptor, ACE2, on the outside of human cells, effectively neutralising it. When tested in cells in the laboratory both antibodies potently neutralised samples of the virus from both outbreaks.

Air pollution risk

Should we be watching our exposure to airborne pollution as well as our cholesterol levels? Research indicates that air pollution has a role to play in atherosclerosis which can contribute to heart attacks or strokes. Findings published in the open access journal, Genome Biology, show how the fats that clog arteries work together with air pollution particles, triggering the genes behind inflammation.

A research team drawn from medical and environmental engineering disciplines at the Universities of California, Los Angeles, investigated the relationship between oxidized phospholipids found in the low density lipoprotein (LDL) particles, the 'bad' fats that clog arteries, and diesel exhaust particles. They exposed cells that line human blood vessels (microvascular endothelial cells) to both exhaust particles and oxidised phospholipids, and measured the effect on genes by using microarray expression profiling. This allowed the identification of gene modules containing a high number of co-expressed genes. These modules appear to be activated by a combination of phospholipids and diesel particles and are linked to vascular inflammation pathways. To confirm these findings, the team exposed mice with high cholesterol levels to the pollutant diesel particles, and saw some of the same gene modules unregulated.

                                  
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