• ICT• Microelectr. & Nanotech• Energy• Life Sciences

InnovationsReportApril 2007

Life sciences- Genes And Biomarkers That Allow Doctors To Choose The Right Therapy For The Right Patient- MicroRNAs Can Be Tumor Suppressors- Breast Cancer Vaccine Stimulates Potent Immune Response To Cancer Cells- - Chromosomes Tell Tale Of Patient's Risk For New, Future Cancer- Blood Cancer Stopped In Mice By Shortening The Ends Of Chromosomes- Targeting Tumors The Natural Way- Improved breast cancer diagnosis- Alzheimer's Genetic Roots Explained- Technology Reveals 'Lock And Key' Proteins Behind Diseases

Energy- Making Gasoline from Carbon DioxideQuantum Secrets of Photosynthesis revealed. Open road for artificial Photosyntesis?- Baking boosts efficiency of plastic solar cells

Microelectr. & Nanotech- Microorganisms act as tiny machines in future MEMS devices- Smallest Organic Light-emitters Created- Super-tough material mimics metal and crystal- Sound solution

ICT- 3-D Chips: IBM Moves Moore's Law Into The Third Dimension- Modified ink printer churns out electronic circuits- The Ultrafast Future of Wireless- Network outpaces internet

Table of contents

ICT

3-D Chips: IBM Moves Moore's Law Into The Third Dimension IBM has announced a breakthrough chip-stacking technology in a manufacturing environment that paves the way for three-dimensional chips that will extend Moore's Law beyond its expected limits. The technology – called "through-silicon vias" -- allows different chip components to be packaged much closer together for faster, smaller, and lower-power systems.

The IBM breakthrough enables the move from horizontal 2-D chip layouts to 3-D chip stacking, which takes chips and memory devices that traditionally sit side by side on a silicon wafer and stacks them together on top of one another. The result is a compact sandwich of components that dramatically reduces the size of the overall chip package and boosts the speed at which data flows among the functions on the chip. "This breakthrough is a result of more than a decade of pioneering research at IBM," said Lisa Su, vice president, Semiconductor Research and Development Center, IBM. "This allows us to move 3-D chips from the 'lab to the fab' across a range of applications." The new IBM method eliminates the need for long-metal wires that connect today's 2-D chips together, instead relying on through-silicon vias, which are essentially vertical connections etched through the silicon wafer and filled with metal. These vias allow multiple chips to be stacked together, allowing greater amounts of information to be passed between the chips. The technique shortens the distance information on a chip needs to travel by 1000 times, and allows for the addition of up to 100 times more channels, or pathways, for that information to flow compared to 2-D chips. IBM is already running chips using the through-silicon via technology in its manufacturing line and will begin making sample chips using this method available to customers in the second half of 2007, with production in 2008. The first application of this through-silicon via technology will be in wireless communications chips that will go into power amplifiers for wireless LAN and cellular applications. 3-D technology will also be applied to a wide range of chips, including those running now in IBM’s high-performance server and supercomputing chips that power the world’s business, government and scientific efforts. In particular, IBM is applying the new through-silicon-via technique in wireless communications chips, Power processors, Blue Gene supercomputer chips, and in high-bandwidth memory applications: 3-D for wireless communications technology: IBM is using through-silicon via technology to improve power efficiency in silicon-germanium based wireless products up to 40 %, which leads to longer battery life. The through-silicon via technology replaces the wire bonds that are less efficient at transferring signals off of the chip.

Power Processors explore 3-D for power grid stability: As we increase the number of processor cores on chips, one of the limitations in performance is uniform power delivery to all parts of the chip. This technique puts the power closer to the cores and allows each core to have ample access to that power, increasing processor speed while reducing power consumption up to 20 %. Bringing 3-D stacking to Blue Gene supercomputing and memory arrays: The most advanced version of 3-D chip stacking will allow high-performance chips to be stacked on top of each other, for example processor-on-processor or memory-on-processor. IBM is developing this advanced technology by converting the chip that currently powers the fastest computer in the world, the IBM Blue Gene supercomputer, into a 3-D stacked chip. IBM is also using 3-D technology to fundamentally change the way memory communicates with a microprocessor, by significantly enhancing the data flow between microprocessor and memory. This capability will enable a new generation of supercomputers. A prototype SRAM design using 3-D stacking technology is being fabricated in IBM's 300 mm production line using 65 nm- node technology.

Modified ink printer churns out electronic circuits

A standard office printer loaded with silver nitrate and vitamin C can produce (clockwise from top-left) mobile phone

antennas, circuits, RFID chips and inductive coils on a range of surfaces A desktop printer loaded with a silver salt solution and vitamin C has been used to produce electronic circuits. The UK researchers behind the feat say their experimental device could pave the way for safer and cheaper electronics manufacturing.Being able to print out electronic components and whole circuit boards could provide an alternative to current manufacturing techniques, which are energy intensive and environmentally unfriendly. Printing conductive polymer ink or pastes containing graphite or metal particles are two existing options. But researchers at Leeds University in the UK wanted to avoid the solvents needed for these processes. They loaded a standard Hewlett Packard ink-jet printer with a solution of metal salts and water. After a pattern is printed using the solution, a chemical known as a reducing agent is then printed over the top to make solid silver form. "We wanted to be able to use a totally water-soluble base," explains team member Matthew Clark. "That allows for much more environmentally friendly processes." They loaded two separate chambers in the printer's cartridge, which normally contain different ink, with the metal solution and the reducing agent. Using silver nitrate solution as the "metal ink" and ascorbic acid (vitamin C) as the reducing agent proved the most successful combination. They then programmed the printer to produce a variety of circuits and radio antennas on different surfaces including paper, cotton and acetate, all of which were placed in the printer like a normal sheet of paper. "One test involved patterning an antenna like that used in a mobile phone on transparent film," says Clark. "It was possible to bend it almost in half without any loss of conductivity." After a circuit is printed using silver nitrate, vitamin C is overlaid a few minutes later. Water can then be used to wash away other products, leaving the silver behind. Scanning electron microscope images reveal a rough surface of silver nanoparticles. Printing the same pattern two or three times improves conductivity because it increases the number of contacts between silver nanoparticles. Desktop printers make images from tiny dots of ink that do not overlap, but bleed slightly into each other, explains Clark: "In future, we'd like to use an industrial jet printer that can so we'll need fewer passes." Scientists agree that ink-jet technology could make new kinds of devices possible. But competing with existing technology could be difficult: "This concept are often simple but there are many challenges to meet. Creating a low enough resistance to match current standards is one of them." But ink-jet printing definitely has a future. Currently, circuit boards and other components are made by etching the desired design out from a layer of metal, which is an energy intensive process. Journal reference: Journal of Micromechanics and Microengineering

The Ultrafast Future of Wireless Researchers at the University of Utah have found a way to control terahertz radiation with more precision than ever before, potentially laying the foundation for a new breed of wireless devices that can take advantage of the previously untapped frequencies. Although still years from commercialization, routers and receivers that use terahertz radiation--which technically ranges from about 100 gigahertz to 10 terahertz--could eventually pack more data onto airwaves, speeding up wireless Internet links a thousand times, says Ajay Nahata, who led the research. Nahata and his team designed a perforated stainless steel film that is able to selectively allow certain terahertz frequencies to pass through and cancel out others. In effect, the researchers have built a simple terahertz filter, a potential precursor to terahertz communication devices. Most wireless gadgets use radiation in the microwave frequency; Wi-Fi, for instance, operates at 2.4 gigahertz. At this frequency, technologies such as radiation sources, detectors, and modulators (devices that encode data on the waves) are well established. But currently, efficient terahertz sources and detectors are still being developed, and "there are effectively no real devices to manipulate those frequencies," says Nahata. "Because of this, terahertz is the gap in the electromagnetic spectrum. We're making new devices so terahertz can be useful. "The benefits of terahertz communication could be great. A typical modulator for a 2.4-gigahertz signal can only encode information at far lower frequencies--at about 50 megahertz. But a 2.4-terahertz wave oscillates a thousand times faster than a 2.4 gigahertz signal, and correspondingly, if terahertz modulators could be made, the modulated signal would also be a thousand times faster, says Nahata. These terahertz waves would be most useful for relatively short-range communication because over greater distances, the signal dies off.

The researchers' new device is essentially a stainless steel metal film with arrays of holes in it. When a terahertz source shines on the film, the radiation gets trapped on its surface. In effect, the energy from the terahertz radiation is converted from a three-dimensional electromagnetic wave to a two-dimensional surface wave, called a plasmon. Nahata explains that as these surface waves move about the film, they can bump into structures on the surface such as troughs and holes. At the holes, he says, the waves constructively interfere, meaning that there is a buildup of light; the energy of the plasmons passes through the holes and is essentially converted back into three-dimensional terahertz radiation, once on the other side of the film. The specific frequency of light that is emitted depends on the spacing of the holes. The concept of using a perforated metal film and plasmons to selectively filter light at specific frequencies is not entirely new, but scientists have assumed that the only way to achieve the transmission of radiation through a film has been to use a uniform, or periodic, array of holes. However, what the Utah researchers showed, in the current issue of Nature, was that the perforations did not need to be uniform at all. In fact, in spite of the seemingly haphazard array of holes, nearly all of the terahertz energy was transmitted through the metal. However, the main benefits of discovering that any array of holes can transmit so much energy, says Nahata, is that it gives more freedom to design filters for various frequencies. Nahata agrees that terahertz communication devices are many years away, but in the meantime, the work could also help researchers better understand terahertz physics and apply it to applications such as safer replacement for x-rays.

Network outpaces internet The University of Wisconsin-Madison has launched a new research network which is up to 20,000 times faster and one million times the capacity of a typical home broadband connection. The Broadband Optical Research, Education and Sciences Network (or BOREAS-Net), forms a loop of fibre optic cable between UW-Madison, Iowa State University, the University of Iowa, and the University of Minnesota. It features two links to Internet2, at Chicago and Kansas City, Missouri. Any outage anywhere in the loop is essentially unnoticed as traffic is rerouted at the speed of light to the other access point. BOREAS' innovative use of this optical network enables its members to manage their own bandwidth and maintain a greater degree of flexibility in supporting research and education services. As programme needs change or new research programmes start, access can be enabled quickly and new paths, or lambdas, can be added without major cost.Other benefits include peering, or trading access at no additional cost. For example, The University of Washington is establishing a dedicated optical network to Kansas City. Once in place, UW-Madison can trade access to Chicago to the University of Washington for access to the west coast without the need for further financial investments.

Microelectronics&

Nanotech

Microorganisms act as tiny machines in future MEMS devices

Electron microscope images of silica-based microshells of several diatom species.

The single-celled Spirostomum is a tiny brown worm that can contract its 500µm-long body to 25% of its length in a milliscend, making this protozoan the fastest-contracting microorganism known. Scientists think of microorganisms like this as tiny functional machines. After all, many of them have capabilities far surpassing the current state-of-the-art in MEMS The integration of microorganisms with MEMS, resulting in “biotic-MEMS,” is a hot topic for scientists designing micron-level machines. Recently, Xiaorong Xiong of Intel, Mary Lidstrom, and Babak Parviz (of the University of Washington) have catalogued a large number of the most promising microorganisms for different areas of MEMS systems. They show that many of these microorganisms can offer capabilities beyond the limits of conventional MEMS technology. “Traditionally, it has always been technology that has come to the aid of biology,” Parviz told “Historically, new technological developments have resulted in the creation of new capabilities to conduct biological studies. Recently, tools and concepts have been increasingly borrowed from biology to solve technology problems. Biological concepts such as self-assembly are under serious consideration by technologists now for making highly integrated nano and micro systems.” The scientists grouped the microorganisms into four areas of use: material synthesis, precise structure formation, as functional devices, and integrated into controllable systems. All the microorganisms studied were less than 1 millimeter in size, and made of one or just a few cells. As the scientists showed, microorganisms have the ability to synthesize at least 64 different inorganic materials used in MEMS technology, in a process called “biomineralization.” Scientists have fossil evidence of this process dating back more than 700 million years. By genetically modifying this process, scientists might be able to produce MEMS materials such as silicon dioxide, biogenic calcite, and magnets. For example, magnetic bacteria naturally synthesize magnetosome crystals, which act as a compass needle inside the bacteria aligning with the earth’s magnetic field. These bacteria always swim in one direction and accumulate in one side of the water, depending on the hemisphere; however, they can also be controlled by an external magnetic field. Compared with conventional MEMS synthesis methods, which often involve high temperatures, corrosive gases, vacuums and plasma, synthesis using microorganisms could be done at room temperature, at near-neutral pH, and in aqueous solutions. Other microorganisms can form intricate structures—such as gold or silver crystals—using a simpler process than conventional photolithography systems. These structures can grow up to three dimensions and be modified with nanoscale precision. Microorganisms can even generate structures a few orders of magnitude larger than themselves,

offering the opportunity to interface with the macroscopic world. The scientists mentioned how the spicules in one deep-sea sponge demonstrate excellent fiber-optical properties. Then there are the microorganisms—like the contracting Spirostomum—that scientists consider as functional devices. One of the most promising areas is in chemical and biological sensors, which use microorganisms that have been evolutionary tailored to detect specific agents—one of the major challenges in MEMS sensor design. Some of these have already been investigated, for purposes such as food and environmental monitoring. “One of the most interesting applications of MOs [microorganisms] in MEMS is to directly use them for detecting chemicals,” said Parviz. “MOs can be genetically engineered to have various receptors. All the transduction and amplification machinery is already in MOs. I think integration of these MOs into MEMS platforms can generate extremely powerful chemical/biological analysis systems.” Other microorganisms can convert chemical energy to generate mechanical forces, such as bacteria that act as free-standing propellers. Others can convert chemical energy to generate electrical energy, such as environmentally-friendly Microbial Fuel Cells for powering robotics and biomedical devices, and for economic hydrogen production. Biotic-MEMS fuel cells may eliminate the difficult task of fabricating and integrating small conventional batteries in MEMS devices. While MEMS technology has had success in fabricating single devices, the scientists explained that a larger challenge is how to integrate these devices into controllable micron-scale systems. Microorganisms offer a unique opportunity as assembled functional systems, if scientists can learn how to take advantage of them, usually by interfacing with microelectronic devices. Scientists have investigated this interface with slightly larger organisms, such as implanting electrodes in the brain of a cockroach to control the insect’s motion, and implants in a rat brain that can enable the rodent to control external devices by transmitting its brain signals. While fascinating, such interfacing work is yet to be explored with microorganisms, where the electronics must be miniaturized even further. The ability to interface with micron-scale robots—i.e. the microorganisms that perform functions—could have significant potential for biotic-MEMS, the scientists predicted.

Smallest Organic Light-emitters Created

Cornell researchers used the process of electrospinning, illustrated here, to create one of the smallest light-emitting

devices to date. A voltage between a microfabricated tip and a substrate ejected a ruthenium-based solution from the tip, creating the thin fibers.

In a collaboration of experts in organic materials and nanofabrication, researchers from Cornell have created one of the smallest organic light-emitting devices to date, made up of synthetic fibers just 200 nm wide The potential applications are in flexible electronic products, which are being made increasingly smaller. The fibers, made of a compound based on the metallic element ruthenium, are so small that they are less than the wavelength of the light they emit. Such a localized light source could prove beneficial in applications ranging from sensing to microscopy to flat-panel displays. The work was published in the February issue of Nano Letters. Using a technique called electrospinning, the researchers spun the fibers from a mixture of the metal complex ruthenium tris-bipyridine and the polymer polyethylene oxide. They found that the fibers give off orange light when excited by low voltage through micro-patterned electrodes -- not unlike a tiny light bulb. The technique can be compared with pouring syrup on a pancake on a rotating table. As the syrup is poured, it forms a spiraling pattern on the flat pancake, which in electrospinning is the substrate with micropatterned gold electrodes. The syrup would be the solution containing the metal complex-polymer mixture in solvent. A high voltage between a microfabricated tip and the substrate ejects the solution from the tip and forms a jet that is stretched and thinned. As the solvent evaporates, the fiber hardens, laying down a solid fiber on the substrate. As scientists look for ways to innovate -- and shrink -- electronics, there is much interest in organic light-emitting devices because they hold promise for making panels that can emit light but are also flexible. "One application of organic light-emitting devices could be integration into flexible electronics," he said. The research also shows that these tiny light-emission devices can be made with simple fabrication methods. Compared with traditional methods of high-resolution lithography, in which devices are etched onto pieces of silicon, electrospinning requires almost no fabrication and is simpler to do.The durability of organic electronics is still under investigation, and this recently completed research is no exception, lead author Craighead said. "The current interest is in the ease with which this material can be made into very small

Super-tough material mimics metal and crystal

Ingots of rhenium diboride are formed by heating and mixing rhenium and boron

A super-hard material that is tough enough to scratch diamond could be made cheaply and easily, a new study suggests. The material is made from the metal rhenium and the element boron and resembles both a metal and a crystal in structure.Diamond is the hardest naturally occurring material known, although researchers have synthesised other substances to rival its hardness. These are generally crystals made from combinations of light elements, including carbon, nitrogen and boron, and are structurally similar to diamond.These materials are better than diamond at some tasks, such as cutting steel, since the carbon in diamond reacts with steel to form iron carbide, dulling the cutting surface. "But all the known super-hard materials are very expensive because they [have to be] made at high pressure," says Sarah Tolbert of the University of California at Los Angeles,. So, together with Richard Kaner and other colleagues, she took a new approach. The team created their material - rhenium diboride – without resorting to high pressures. "We wanted to change the ease with which hard materials are made," Tolbert says. First of all, they considered what makes substances hard. Metals are difficult to compress because their atoms carry dense coats of electrons that repel neighbouring atoms, although this means they can still bend. On the other hand, the atoms in stiff crystals such as diamond have bonds in rigidly prescribed directions, which create a strong, regular scaffold that resists bending, skewing or breaking.Tolbert and colleagues devised a way to incorporate both these properties. They combined rhenium, a hard-to-compress metal, with boron, which forms strong bonds with rhenium to create a highly incompressible material that also has a rigid scaffold of bonds on the inside. They heated and mixed rhenium and boron powder in a furnace and ran a large electric current through the mixture. This quickly melted the materials, allowing ingots a few centimetres across to form. The ingots appear shiny like a metal but are also extremely hard, as measured by how much they resist being indented by a diamond tip. The material is nearly as hard as cubic boron nitride and boron suboxide, two of the hardest materials known, and like them can scratch diamond. It should also be able to cut steel without reacting chemically with the iron. "The novelty of this is that they've come up with this hybrid approach [to making extremely hard materials]. I think this is just the tip of the iceberg for this family of materials." Journal reference: Science

Sound solution Researchers working on materials at the Fraunhofer Institute for Structural Durability and System Reliability in Darmstadt have devised a window that not only blocks out high and low-frequency noises but also actively cancels them out. Sound waves are patterns of pressure transmitted through the air. When the pressure waves hit a building they cause it to vibrate and these waves are transmitted through the fabric of the building into the air inside.The most efficient materials for transmitting the sound are glass and metal; curtain-wall buildings, where the outer skin is composed entirely of glass attached to a steel frame, are particularly vulnerable. Passive vibration dampers can be attached to the buildings but, as with the double glazing, this is not a perfect solution. The only other way to prevent the transmission of bass frequencies is to increase the thickness of the glass but this is heavy, and the support framework of curtain-wall constructions cannot support it. The Fraunhofer team, working with researchers from the Darmstadt University of Technology, has developed a method that can prevent both window vibration and the transmission of sound vibration from steel structures to glass. Effectively an active soundproof window, the equipment is particularly effective at low frequencies of 50-1,000Hz, typical of the low-frequency noise of jet engines, traffic or bass-heavy music. The key to the active soundproofing is piezoelectric crystals, which flex when an electric current is applied to them. The team, led by Thilo Bein, attached sensitive accelerometers to the window frames and the glass, which measure the vibrations generated by noise. These are connected to an electronic oscillator which vibrates a piezoelectric strip placed close to where the window meets the frame. The oscillations are phased so they cancel out the vibrations caused by the incoming noise. The result - in theory - is that the glass remains completely still, preventing the transmission of the noise. In practice, not all of the noise is blocked. But the results are still impressive. 'Tests have shown that our windows are capable of lowering noise levels by an average of 6dB,' said Bein. 'We're concentrating on the frequency range of 50-500Hz, which is particularly troublesome. The perceived noise inside is only half as loud.' For some frequencies, he added, the noise reduction is as high as 15dB. Bein's team has also adapted the system to prevent transmission via the frame of the building. the method is the same, but the frame incorporates stacks of piezoelectric chips that impart a bending movement to the steel, again preventing the vibration from reaching the outer cladding. 'These systems are designed mainly for apartment blocks, hotels and offices near airports and main roads,' said Bein. 'In principle it works for any sort of windows; it's embedded in the frame, near to the glass, and it's almost invisible. We're working on using transparent ceramics that could be embedded in the glass itself. They could be used in normal residential buildings - it's simply a matter of cost.'He added that the systems could be on the market within four years.

Energy

Making Gasoline from Carbon Dioxide A solar-powered reaction turns a greenhouse gas into a valuable raw material.

Solar splitter: An amber-colored semiconductor (gallium phosphide), together with metal contacts

Researchers at the University of California, San Diego recently demonstrated that light absorbed and converted into electricity by a silicon electrode can help drive a reaction that converts carbon dioxide into carbon monoxide and oxygen. Carbon monoxide is a valuable commodity chemical that is widely used to make plastics and other products, says author Clifford Kubiak. It is also a key ingredient in a process for making synthetic fuels, including syngas (a mixture largely of carbon monoxide and hydrogen), methanol, and gasoline. At least at first, such a process will not make a significant impact on reducing greenhouse gases in the atmosphere--that would take quite large-scale operations, Kubiak says. But "any chemical process that you can develop that uses CO2 as a feedstock, rather than having it be an end product, is probably worth doing." The system may also be part of a solution to a continuing problem with solar energy. For solar panels to be useful when the sun isn't shining, the electricity they produce has to be stored. A potentially practical way of doing that is by converting the electrical energy into chemical energy. One popular approach is to use solar cells to produce hydrogen, which could then be used in fuel cells. But hydrogen gas is much more difficult to transport and store than are liquid fuels, such as gasoline, which contain far more energy by volume than hydrogen does. The UCSD system shows that it is possible to use solar energy to make carbon monoxide that then, together with hydrogen, can be converted into gasoline. Currently, carbon monoxide is made from natural gas and coal. But carbon dioxide is a more attractive raw material in part because it's very cheap, indeed, it's something industrial companies will pay to get off their hands. In the prototype device, sunlight passes through carbon dioxide dissolved in a solution before being absorbed by a semiconductor cathode, which converts photons into electrons. Aided by a catalyst, the electrons react with carbon dioxide to form carbon monoxide at the electrode. At the anode, a catalyst made of platinum, water is converted into oxygen. To make a fuel, the carbon monoxide can be combined with hydrogen to create syngas in a well-known technology called the Fischer-Tropsch process, which has been widely used to make gasoline from coal. With the new process for creating syngas, however, fossil fuels could be unnecessary. The system, which Kubiak began developing as a way of manufacturing oxygen for manned missions to Mars, is still a work in progress. In the first prototype, only about half of the energy needed for the reactions was supplied by the sun, with the rest coming from outside electricity. That's because the researchers decided to prove the concept using silicon as the semiconductor. They are now working with a gallium-phosphide semiconductor, which has exactly the right electronic properties to drive the necessary reactions using sunlight alone. At this early stage--Kubiak says that commercial systems could be 10 years away, the efficiency and economics of making fuels this way aren't known. Kubiak says it's likely that for large-scale applications, his group will need to use catalyst-coated nanoparticles to increase surface area, speeding up reactions.

Quantum Secrets of Photosynthesis revealed. Open road for artificial Photosyntesis? Through photosynthesis, green plants and cyanobacteria are able to transfer sunlight energy to molecular reaction centers for conversion into chemical energy with nearly 100-% efficiency. Speed is the key – the transfer of the solar energy takes place almost instantaneously so little energy is wasted as heat. How photosynthesis achieves this near instantaneous energy transfer is a long-standing mystery that may have finally been solved.

Sunlight absorbed by bacteriochlorophyll (green) within the FMO protein (gray) generates a wavelike motion of

excitation energy whose quantum mechanical properties can be mapped through the use of 2D electronic spectroscopy. A study led by researchers with the U.S. Department of Energy’s Lawrence Berkeley National Laboratory and the University of California at Berkeley reports that the answer lies in quantum mechanical effects. Results of the study are presented in the current issue ofture. “We have obtained the first direct evidence that remarkably long-lived wavelike electronic quantum coherence plays an important part in energy transfer processes during photosynthesis,” said Graham Fleming, the principal investigator for the study. “This wavelike characteristic can explain the extreme efficiency of the energy transfer because it enables the system to simultaneously sample all the potential energy pathways and choose the most efficient one.” In the new study, he and his collaborators report the detection of “quantum beating” signals, coherent electronic oscillations in both donor and acceptor molecules, generated by light-induced energy excitations, like the ripples formed when stones are tossed into a pond. Electronic spectroscopy measurements made on a femtosecond time-scale showed these oscillations meeting and interfering constructively, forming wavelike motions of energy (superposition states) that can explore all potential energy pathways simultaneously and reversibly, meaning they can retreat from wrong pathways with no penalty. This finding contradicts the classical description of the photosynthetic energy transfer process as one in which excitation energy hops from light-capturing pigment molecules to reaction center molecules step-by-step down the molecular energy ladder.“The classical hopping description of the energy transfer process is both inadequate and

inaccurate,” said Fleming. “It gives the wrong picture of how the process actually works, and misses a crucial aspect of the reason for the wonderful efficiency.” The photosynthetic technique for transferring energy from one molecular system to another is one of Nature’s spectacular accomplishments. If we can learn enough to emulate this process, we might be able to create artificial versions of photosynthesis that would help us effectively tap into the sun as a clean, efficient, sustainable and carbon-neutral source of energy. Towards this end, Fleming and his research group have developed a technique called 2D electronic spectroscopy that enables them to follow the flow of light-induced excitation energy through molecular complexes with femtosecond temporal resolution. The technique involves sequentially flashing a sample with femtosecond pulses of light from three laser beams. A fourth beam is used as a local oscillator to amplify and detect the resulting spectroscopic signals as the excitation energy from the laser lights is transferred from one molecule to the next. Fleming has compared 2-D electronic spectroscopy to the technique used in the early super-heterodyne radios, where an incoming high frequency radio signal was converted by an oscillator to a lower frequency for more controllable amplification and better reception. In the case of 2-D electronic spectroscopy, scientists can track the transfer of energy between molecules that are coupled (connected) through their electronic and vibrational states in any photoactive system, macromolecular assembly or nanostructure. Fleming and his group first described 2-D electronic spectroscopy in 2005, when they used the technique to observe electronic couplings in the Fenna-Matthews-Olson (FMO) photosynthetic light-harvesting protein, a molecular complex in green sulphur bacteria. “That was the first biological application of this technique, now we have used 2-D electronic spectroscopy to discover a new phenomenon in photosynthetic systems. While the possibility that photosynthetic energy transfer might involve quantum oscillations was first suggested more than 70 years ago, the wavelike motion of excitation energy had never been observed until now.”. In the new study, the FMO protein was again the target. FMO is considered a model system for studying photosynthetic energy transfer because it consists of only seven pigment molecules and its chemistry has been well characterized. “To observe the quantum beats, 2-D spectra were taken at 33 population times, ranging from 0 to 660 femtoseconds,” said Engel. “In these spectra, the lowest-energy exciton (a bound electron-hole pair formed when an incoming photon boosts an electron out of the valence energy band into the conduction band) gives rise to a diagonal peak near 825 nm that clearly oscillates. The associated cross-peak amplitude also appears to oscillate. Surprisingly, this quantum beating lasted the entire 660 femtoseconds.” Engel said the duration of the quantum beating signals was unexpected because the general scientific assumption had been that the electronic coherences responsible for such oscillations are rapidly destroyed. “For this reason, the transfer of electronic coherence between excitons during relaxation has usually been ignored,” Engel said. “By demonstrating that the energy transfer process does involve electronic coherence and that this coherence is much stronger than we would ever have expected, we have shown that the process can be much more efficient than the classical view could explain. However, we still don’t know to what degree photosynthesis benefits from these quantum effects.” Engel said one of the next steps for the Fleming group in this line of research will be to look at the effects of temperature changes on the photosynthetic energy transfer process. The results for this latest paper in Nature were obtained from FMO complexes kept at 77 K. The group will also be looking at broader bandwidths of energy using different colors of light pulses to map out everything that is going on, not just energy transfer. Ultimately, the idea is to gain a much better understanding how Nature not only transfers energy from one molecular system to another, but is also able to convert it into useful forms. “Nature has had about 2.7 billion years to perfect photosynthesis, so there are huge lessons that remain for us to learn,” Engel said. “The results we’re reporting in this latest paper, however, at least give us a new way to think about the design of future artificial photosynthesis systems.”

Baking boosts efficiency of plastic solar cells Heating plastic solar cells can alter their structure in a way that boosts efficiency, new research shows. The US and Korean scientists behind the discovery say it could ultimately allow flexible, lightweight plastic cells to replace rigid traditional cells. Solar cells are usually made from silicon, which is inflexible and relatively heavy. By contrast, plastic solar cells could be more easily supported and wrapped around surfaces (see Pliable solar cells are on a roll). It might even be possible to spray light-collecting plastic onto a surface.Plastic cells lag behind silicon in terms of efficiency, however, at best converting just 5% of solar energy into electricity compared with up to 40% for conventional cells. "To make plastic cells commercially viable, you need to reach about 8%," says David Carroll of Wake Forest University in Winston-Salem, US. "That matches some silicon products already on the market." The best plastic solar cells are made from a light-absorbing polymer containing soccer ball-shaped carbon molecules called fullerenes. The fullerenes provide stepping stones in the plastic film for charge to hop across. Space charge The main efficiency-limiting factor is a kind of electrical "traffic jam" that occurs inside the plastic. "When you draw off the electrons freed when light hits these devices you leave behind an absence of electrons we call 'space charge'," Carroll told. This presents a barrier to other electrons. "Charge isn't mobile enough in these materials to fill the gap and everything gets blocked up," he adds. Carefully heating plastic cells seems to solve this problem. Working with colleagues from Wake Forest University, and from the Korea Institute of Science and Technology in Seoul, Carroll found that heating can introduce crystal patterns into the plastic to diffuse these jams. "It's possible to create little 'highways' that prevent space charge from building up," Carroll says. Crystal whiskers By carefully heating finished cells to around 150ºC, Carroll and colleagues made the fullerene molecules form whiskers of crystal. These trigger crystallisation in the surrounding polymer as well. The fullerene-and-polymer crystal creates a network across the cell, allowing charge to move easily and preventing space charge blockages. "Getting around space charge is a big step," says Carroll. The heating process can increase efficiency from 5% to 6%. "Some performed as well as 7%," Carroll told. "We think we can probably push it up to 10%." This could pave the way for commercially viable plastic solar cells, he says. The research will appear in a forthcoming edition of the journal Applied Physics

Life Sciences

Genes And Biomarkers That Allow Doctors To Choose The Right Therapy For The Right Patient Genetic and epigenetic variations ensure that no two people are exactly alike, and the same holds true for any two cancers. Now, researchers have the tools and the knowledge to help predict how individuals will respond to cancer therapies, enabling them to create more effective therapies for individual cancers -- personalized medicine. At the 2007 Annual Meeting of the American Association for Cancer Research, researchers present new biomarkers -- and techniques for determining biomarkers -- that could determine how an individual might respond to drug or radiation therapy. A new high-throughput genetic analysis technique can reveal gene markers -- by the dozens -- that determine how a patient might respond to certain cancer drugs, according to scientists at the Translational Genomics Research Institute (TGen). The TGen researchers have found 164 genes that are involved in regulating the sensitivity of squamous cell head and neck cancer cells to lapatinib, a cancer drug that was recently approved for use in metastatic breast cancer under the name Tykerb. The study, a collaboration with GlaxoSmithKline, evaluated 7,000 genetic targets in human head and neck cancer cells to discover specific genes that might shade an individual's response to Tykerb. "Our goal is to apply advanced cellular genomic strategies to assist clinical drug development by finding gene states that predict a patient's response to a specific drug, and which combination of drugs produce the most favorable response." said Spyro Mousses, at TGen. "In this study, we were able to discover new candidate gene states that may be useful in determining a patient's sensitivity or resistance to Tykerb, and the results have revealed several sensitizing drug targets that reveal a set of candidate combination drugs that are predicted to be synergistic with Tykerb." Tykerb is an enzyme inhibitor that effectively blocks two cell receptors, ERBB2 and EGFR, from receiving molecular signals. By blocking these signals, Tykerb could effectively shut down the growth of solid tumors, such as those found in breast, lung and head and neck cancer. However, molecular mechanisms within the cell, largely determined by genetics, could determine how effective cancer drugs are for a particular recipient, Mousses said. To search for target genes that regulate Tykerb response, Mousses and his colleagues performed a genome-scale scan of two cancer cell lines using high-throughput RNAi, "interfering" RNA strands that bind to and knock out one gene individually, across the genome. It is a systematic and highly efficient technique that uses high-speed mechanization to quickly evaluate how specific genes might affect the cell's sensitivity to an agent, Tykerb in this case. The TGen researchers are currently in the process of refining their genetic "hits" and learning more about how cancer specific variations in these sensitizing genes might further affect Tykerb response. While their findings are still at a preliminary stage, Mousses and his colleagues believe their studies will provide important insights into how to predict oncology drug response and much needed genomic intelligence to support commercial drug development.

MicroRNAs Can Be Tumor Suppressors University of Virginia researchers have discovered that microRNAs, a form of genetic material, can function as tumor suppressors in laboratory studies. In the current issue of Genes & Development, UVa researchers Drs. Yong Sun Lee and Anindya Dutta have shown that microRNAs can suppress the overexpression of a gene called HMGA2. This gene is related to creation of fatty tissue and certain tumors, as well as diet-induced obesity. MicroRNA is a single-stranded RNA that is typically only 20-25 nucleotides long and is related to regulating the expression of other genes. "Overexpression of the HMGA2 gene is an essential feature of many medically significant tumors, such as uterine fibroids," explains Dr. Dutta. "It is very exciting to realize that microRNAs have an important role in suppressing the overexpression of HMGA2. Thus, they may also have a role in causing, and perhaps curing, a disease that is responsible for the vast majority of hysterectomies in the Western world." Studying chromosomal HMGA2 translocations that are associated with human tumors, the researchers found that, in normal cells, a microRNA called let-7 binds to the 3' end of the HMGA2 mRNA transcript and suppresses its expression in the cell cytosol. However, chromosomal breaks that shorten the 3' end of the HMGA2 transcript,and prevent let-7 binding, result in aberrantly high levels of HMGA2 expression and tumorigenesis (formation of tumors). This paper establishes that HMGA2 is a target of let-7, and that the let-7 microRNA functions as a tumor suppressor to prevent cancer formation in healthy cells.

Breast Cancer Vaccine Stimulates Potent Immune Response To Cancer Cells Mayo Clinic researchers have designed a new strategy in the promising field of cancer vaccine research that's proven to be successful in boosting T cells -- the immune builders akin to a super defense force against cancer cells. Scientists say their strategy may prove to be more successful than methods currently under study and in clinical trials. Using vaccines to prevent or slow the growth of cancerous tumors is based on the premise that the body's immune system can be strengthened with an engineered vaccine that would stimulate an antibody and cellular response against cancer cells. Cancer vaccines are still considered experimental and so far, research results have been mixed. New studies, such as this, demonstrate that researchers are closing in on designing viable cancer vaccines, the investigators say. In this study, Pilar Nava-Parada, and colleagues designed a synthetic peptide vaccine that stimulated an anti-tumor T cell response that recognized and successfully waged a battle against the spread of breast cancer cells in mouse models. (T cells are white blood cells with a key function in immune response.) In female mouse models bred with the cancer-producing oncogene HER-2/neu, researchers administered a synthetic peptide vaccine during the early stage of tumor development. The experiment was effective in 100 percent of the study samples by either slowing or stopping the progression of breast cancer. In at least one case, the vaccine worked for as long as 39 weeks. Because the use of synthetic peptides alone generally does not trigger a strong immune response, researchers administered the vaccine in combination with a Toll-like receptor stimulant that is designed to mimic the way in which an invading bacterial agent would induce an immune response in humans. Under normal conditions, the response is generally strong enough for the body to recognize and attack invading bacteria. Researchers used this strategy, but also introduced anti-CD25 antibodies to increase the immune response. These antibodies control the production of T regulatory cells that can prevent the vaccine from doing its job, but by combining the two strategies (immunization and depletion of T regulatory mechanisms), the vaccine successfully passed through the T cell checkpoint. This approach was successful in stimulating an effective immune response. "We found that we could train the immune system to recognize these synthetic peptides as dangerous foreign agents of the HER-2/neu gene by mimicking what the bacteria would do in your body. The body responded by killing everything that expressed HER-2/neu in high amounts," Dr. Nava-Parada said. In addition, "we estimate that in a real life scenario, we could probably use this technique to decrease the number of immunizations a patient would need (one instead of three), to build an immune response strong enough to destroy the tumor. Up until now, researchers undertaking similar work have only been able to get vaccines to work in about 30 percent of HER-2/neu study models, but only by depleting T regulatory cells, which can have negative side effects, such as an autoimmune disorder.In our study we showed that we can prevent tumors without depleting these cells and can achieve this success only by using a bacterial-like adjuvant administered with the right peptide.". In addition, Dr. Nava-Parada said that other studies fail to accurately represent human cancers because they measure acute rejection of a tumor cell line that is produced in the laboratory and then injected into healthy animal models. Study models like the one described in this AACR presentation are thought to be more realistic because the study considers the entire natural history of the tumor in an animal that harbors the HER-2/neu gene."When the animal has a precancerous lesion, we vaccinate it and closely follow the appearance of the spontaneous tumor through its life. Conducting the research in this manner allows us to gain a clearer insight into a real-life cancer patient's situation," she said. Cancer vaccines are intended for patients with a strong genetic predisposition or personal history of cancer; patients who do not respond to traditional therapies; or, as a preventive measure for patients who have successfully completed traditional courses of treatment, such as surgery, radiation and/or chemotherapy.

Chromosomes Tell Tale Of Patient's Risk For New, Future Cancer Hodgkin's disease survivors who have greater genetic instability in their white blood cells are two-and-a-half times more likely to develop another type of cancer, researchers from The University of Texas M. D. report at the American Association for Cancer Research annual meeting. Chromosomal aberrations analyzed by the researchers could potentially be used as a biomarker to predict a person's risk of developing a second primary tumor, both for Hodgkin's disease patients and for those with other types of cancer, says principal investigator Randa El-Zein. "Hodgkin's disease is a highly treatable cancer of the lymphatic system and many patients do very well. Yet we know that some patients are at risk of developing another type of cancer later on - solid tumors, leukemia or melanoma, for example - and we cannot identify those patients in advance now.We can use this measure of genetic instability to identify patients at high risk and counsel them to continue regular screening for breast, colon and other cancers even after their Hodgkin's disease has disappeared," El-Zein says. "We also can emphasize that they should especially avoid tobacco use or exposure to environmental toxins at work and eat a healthy diet. You're at risk, don't do anything to make it worse." The research team looked at 252 adults treated for Hodgkin's disease at M. D. Anderson between 1986 and 1992. The patients had cytogenetic analysis - a close look at the chromosomes in their lymphocytes - done before treatment began and periodically throughout their care. "We found that people with a higher level of chromosomal aberrations are the ones who developed a second primary tumor," El-Zein notes. The team measured chromosomal breaks per 100 cells and found patients who developed a second primary cancer had 5.91 breaks per 100 cells while those who did not develop a second tumor had 3.97 breaks per 100. Over a median follow-up period of 13 years, 27 of the patients developed second cancers: five solid tumors, four leukemias, 11 skin cancers and seven lymphomas. Those with higher chromosomal breaks were 2.48 to 2.78 times more likely to develop cancer anew. Chromosomal breaks occur when both chromosome arms are truncated. Chromatid breaks are those when only one chromosome arm is shortened, yet these appear to be the more predictive type of break, the researchers found. "Whatever can be applied to Hodgkin's can be applied to other cancers," El-Zein said, so chromosomal screening has potentially broad application for gauging second primary cancer risk across types of cancer. The team is also analyzing chromosomal breaks for correlations to a patient's response to treatment.

Blood Cancer Stopped In Mice By Shortening The Ends Of Chromosomes A Johns Hopkins team has stopped a form of blood cancer in its tracks in mice by engineering and inactivating an enzyme, telomerase, thereby shortening the ends of chromosomes, called telomeres. "Normally, when telomeres get critically short, the cell commits suicide as a means of protecting the body," says author Carol Greider. Her study, appearing in the current issue of Cancer Cell, uncovers an alternate response where cells simply - and permanently - stop growing, a process known as senescence. In an unusual set of experiments, the research team first mated mice with nonoperating telomerase to mice carrying a mutation that predisposed them to Burkitt's lymphoma, a rare but aggressive cancer of white blood cells. Telomerase helps maintain the caps or ends of chromosomes called telomeres, which shrink each time a cell divides and eventually - when the chromosomes get too short - force the cell to essentially commit suicide. Such cell death is natural, and when it fails to happen, the result may be unbridled cell growth, or cancer. The first generation pups born to these mice contained no telomerase and very long telomeres. These mice all developed lymphomas by the time they were 7 months old. The researchers then continued breeding the mice to see what would happen in later generations. By the fifth generation, the researchers discovered that the mice had short telomeres and stopped developing lymphomas. When the researchers blocked the suicide machinery in these fifth-generation mice, they were very surprised to find that the mice still remained cancer free. "We were confused as to what was going on; we thought for sure that blocking the cells' ability to commit suicide would lead to the cancer's returning," says Greider. A closer look showed microtumors in the mice's lymph nodes that had begun the road to cancer, but stopped, falling instead into a state of senescence. "They don't die, they don't divide, they just sit there in permanent rest," says Greider. Greider, who won the Lasker Award in 2006 for her discovery of telomerase, says further study of the road to senescence should suggest new ways of preventing or treating cancer by interfering safely with telomerase and the cell-suicide system.

Targeting Tumors The Natural Way By mimicking Nature's way of distinguishing one type of cell from another, University of Wisconsin-Madison scientists now report they can more effectively seek out and kill cancer cells while sparing healthy ones. The new tumor targeting strategy cleverly harnesses one of the body's natural antibodies and immune responses. "The killing agent we chose is already in us," says UW Laura Kiessling, who led the work. "It's just not usually directed toward tumor cells." In a series of cell-based experiments, the researchers' system recognized and killed only those cells displaying high levels of receptors known as integrins. These molecules, which tend to bedeck the surfaces of cancer cells and tumor vasculature in large numbers, have become important targets in cancer research. In contrast, an established tumor-homing agent linked to the cell toxin doxorubicin destroyed cells even when they expressed very little integrin, indicating this strategy has the potential to kill cancerous and healthy cells indiscriminately. "This study suggests that the cell recognition mode we used can direct an endogenous immune response to destroy cancer cells selectively," says Kiessling. "We think this could lead to a new class of therapeutic agents not only for cancer but also for other diseases involving harmful cells." Cancer cells typically display higher levels of certain receptors on their surfaces than do normal cells, a fact that allows scientists to pinpoint tumor cells lurking among the body's scores of cell types. A popular approach employs a cell-binding agent, such as a monoclonal antibody, that is powerfully attracted to the target receptor and holds fast to any cell displaying it. Although this strategy has benefits, it's not natural, says Kiessling. Cell recognition in living systems instead involves binding agents that attach only weakly to any single target receptor, and thus stick to cells only when several receptors are displayed together. These weak "multivalent" interactions cut down on cases of mistaken identity, because if the agent contacts the wrong cell type, it can be easily displaced. The team got the idea to mimic this process from efforts to transplant pig organs into primates. The surfaces of most mammalian and bacterial cells express large amounts of a carbohydrate, called alpha-Gal in scientific shorthand, while the cells of humans and other higher primates do not. What humans and primates do produce in abundance is an antibody against the carbohydrate, called anti-Gal. When scientists tried transplanting pig organs into primates, the anti-Gal antibodies bound to the alpha-Gal on the organ's cells, unleashing a potent immune response that caused immediate organ rejection. But true to natural cell recognition, the immune response occurs only when clusters of many alpha-Gal molecules are present for anti-Gal to bind with. Armed with this knowledge, Kiessling's group modified an agent known to bind tightly to integrin and tethered it to alpha-Gal. When they mixed this molecule with cells displaying high levels of integrin, the agent, by attaching to the receptor, decorated the cells with large amounts of alpha-Gal. In cell cultures containing human serum, the alpha-Gal then elicited the cell-destroying immune reaction. In cells with low concentrations of integrin, the agent still bound, but the resulting levels of alpha-Gal weren't sufficient to elicit the immune response, and the cells survived. The same wasn't true if the cell-binding agent delivered doxorubicin to cells instead: They were killed regardless of the amount of integrin they carried. Because target receptors on cancer cells usually reside on healthy cells, too - albeit in lower numbers - therapies aimed at these receptors are always expected to have debilitating side effects. That's why Kiessling's approach holds such promise.

Improved breast cancer diagnosis By combining magnetic resonance imaging (MRI) and near-infrared optics, researchers at Dartmouth College and Dartmouth Medical School, New Hampshire may have devised a more accurate method for diagnosing breast cancer. Their pilot study, demonstrating the feasibility of the concept, is published in the current issue of the journal Optics Letters. The new technique is said to utilise MRI to produce an image of the breast, yielding information on its structure, including shape and composition. The near-infrared light technique provides information on how the tissue is functioning, for example, whether a region contains a large amount of blood and is rapidly consuming oxygen as early cancers typically do. The researchers are hoping this dual-procedure approach will be a key to learning which tissues are malignant before performing a biopsy. The pilot study involved a 29-year-old woman with a ductal carcinoma, a very common breast cancer, in her left breast. A contrast MRI procedure was performed, where MRI was done before and after the contrasting agent gadolinium was injected. The area enhanced by the contrasting agent was targeted for the optical technique, known as near-infrared spectroscopy (NIRS). The results showed the area's haemoglobin level was high, oxygen saturation was low and water content was high, all indicators of cancerous tissue. Recent advancements in medical imaging systems have focused on increasing the detail of anatomical images, but there has also been a growing interest in devices that provide information on tissue function. One of the difficulties with functional imaging has been that most of these devices have low spatial resolution. The structural information from the MR image helps guide the NIRS technique to the regions of interest so that the two can together create high-resolution, functional images of breast cancer.

Alzheimer's Genetic Roots Explained Scientists have known for more than a decade that individuals with a certain gene are at higher risk for developing Alzheimer’s disease. Now a new study helps explain why this is so. The research, led by scientists at the Oklahoma Medical Research Foundation (OMRF), has uncovered a molecular mechanism that links the susceptibility gene to the process of Alzheimer’s disease onset. The findings appear in the current issue of The Journal of Neuroscience and may lead to new pathways for development of Alzheimer’s therapeutics. Approximately 15 % of the population carries a gene that causes their bodies to produce a lipoprotein—a combination of fat and protein that transports lipids in the blood—known as apolipoprotein(ApoE4) . Studies have found that those who inherit the E4 gene from one parent are 3 times more likely than average to develop Alzheimer’s, while those who get the gene from both parents have a tenfold risk of developing the disease. In the new study, OMRF’s Jordan J.N. Tang discovered that ApoE4 (along with other apolipoproteins) attaches itself to a particular receptor on the surface of brain cells. That receptor, in turn, adheres to a protein known as amyloid precursor protein. The brain cells then transport the entire protein mass inside. Once inside, cutting enzymes, called proteases, attack the amyloid precursor protein. These cuts create protein fragments that, when present in the brain for long periods of time, are believed to cause the cell death, memory loss and neurological dysfunction characteristic of Alzheimer’s.

In the brain, fatty molecules known as ApoE4 (red) collide with brain cells, whose surfaces are also home to complex

masses consisting of proteins and cutting enzymes (Fig 1). When this happens, ApoE4 then attaches itself to a receptor on the surface of brain cells that, in turn, adheres to the mass. The brain cells then transport the entire protein mass

inside (Fig 2). Once inside, the cutting enzymes attack the protein mass, creating the tangles of protein fragments (yellow) believed to cause Alzheimer's disease (Fig 3)

Although researchers have known for more than a decade that ApoE4 was involved, somehow, in development of Alzheimer’s, Tang’s new study is the first to connect the process of protein fragment formation to ApoE4. While roughly 1 in 7 people carry the E4 gene, the rest of the population carry only two variations, known as E2 and E, of that gene. These individuals have a markedly lower incidence of Alzheimer’s than those who carry the E4 gene. The new study found that ApoE4 produced more protein fragments than did E2 or E3.“ApoE4 apparently interacts better with the receptor than its cousins,” said Tang. “This may explain why people who carry the E4 gene have a higher risk of developing Alzheimer. These findings may allow us to investigate the possibility of therapeutic intervention at different points in the process. For example, such efforts might focus on developing a compound to interfere with the receptor’s ability to adhere to ApoE4.There currently is no effective treatment for Alzheimer’s disease, so we must explore every possible option to find a way to stop it. This work opens the door to the development of alternate methods for treating Alzheimer’s. ApoE4 also has been linked to coronary artery disease. Ultimately, this work could pave the way for similar study of the pathogenesis of other diseases,”

Technology Reveals 'Lock And Key' Proteins Behind Diseases A new technology developed at the University of Toronto is revealing biochemical processes responsible for diseases such as cystic fibrosis and could one day pave the way for pharmaceutical applications.

Positive match: The "iMYTH-system" showing a positive readout. If two proteins interact in the iMYTH system the yeast

cell will stain blue. A study appearing in the current issue of Molecular Cell describes how U of T and Johns Hopkins University researchers designed a device to test for proteins that play an important role in human health and disease. The technology, iMYTH (or integrated membrane yeast-two hybrid system), scans cells to detect proteins that interact with key proteins called ATP-binding cassette (ABC) transporters -- proteins that, when impaired, can cause disease. One of the best known ABC transporters is the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which, when disabled by mutation, causes cystic fibrosis, a hereditary disease that results in progressive disability and early death. Another important ABC protein is the Multidrug Resistance Protein (MRP), which normally removes drug metabolites and toxins from cells in our bodies but when overzealous can contribute to the drug resistance of tumours, thereby thwarting chemotherapy. "All the cells in our bodies contain transporters that are poised in cellular membranes and act as 'gatekeepers' to allow the entry of certain substances, like nutrients, into the cell and promote the export of other substances, like toxins, out of the cell," says Professor Igor Stagljar, lead author of the study. "When the function of these transporters is impaired, disease can result. This device gives us insights as to what proteins are interfering with this process." iMYTH works by scanning cells to reveal proteins that fit with the transporters, the only screening system sophisticated enough to work with delicate membrane proteins. Simply, if two proteins interact in iMYTH, they will stain the yeast cell blue. "Like lock and key, if two proteins interact with one another, it is safe to assume they participate or regulate the same cellular process," explains Stagljar. "Identifying new interactors for ABC transporters may reveal unanticipated aspects of how these transporters function and help researchers gain clues for fighting disease and drug resistance." Using iMYTH, the Stagljar lab identified six proteins that interact with and presumably communicate with the ABC transporter Ycf1p, a yeast version of the human proteins CFTR and MRP. These newly discovered protein interactors represent novel potential pharmaceutical targets. Through a series of biochemical and genetic tests, the researchers discovered that one of these interactors, Tus1p, regulates Ycf1p transporter function in a completely novel way to stimulate its ability to remove toxins from the cell. "The more we learn about membrane proteins, the better we can use this knowledge for pharmacological and clinical applications," Stagljar says. "We work by putting together biochemical processes piece by piece like a puzzle. Hopefully soon we will have a complete picture of how many other diseases such as breast cancer, heart diseases, arthritis and schizophrenia are caused by mutations in various human membrane proteins."