2014 Nobel Prize in Physiology or Medicine: Cells that constitute a positioning system in the brain

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How do we know where we are? How can we find the way from one place to another? And how can we store this information in such a way that we can immediately find the way the next time we trace the same path? This year´s Nobel Laureates have discovered a positioning system, an “inner GPS” in the brain that makes it possible to orient ourselves in space, demonstrating a cellular basis for higher cognitive function.

In 1971, John O´Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus that was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. O´Keefe concluded that these “place cells” formed a map of the room.

More than three decades later, in 2005, May-Britt and Edvard Moser discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they called “grid cells,” that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate.

The discoveries of John O´Keefe, May-Britt Moser and Edvard Moser have solved a problem that has occupied philosophers and scientists for centuries — how does the brain create a map of the space surrounding us and how can we navigate our way through a complex environment?

How do we experience our environment?

The sense of place and the ability to navigate are fundamental to our existence. The sense of place gives a perception of position in the environment. During navigation, it is interlinked with a sense of distance that is based on motion and knowledge of previous positions.

Questions about place and navigation have engaged philosophers and scientists for a long time. More than 200 years ago, the German philosopher Immanuel Kant argued that some mental abilities exist as a priori knowledge, independent of experience. He considered the concept of space as an inbuilt principle of the mind, one through which the world is and must be perceived. With the advent of behavioural psychology in the mid-20th century, these questions could be addressed experimentally. When Edward Tolman examined rats moving through labyrinths, he found that they could learn how to navigate, and proposed that a “cognitive map” formed in the brain allowed them to find their way. But questions still lingered — how would such a map be represented in the brain?

John O´Keefe and the place in space

John O´Keefe was fascinated by the problem of how the brain controls behaviour and decided, in the late 1960s, to attack this question with neurophysiological methods. When recording signals from individual nerve cells in a part of the brain called the hippocampus, in rats moving freely in a room, O’Keefe discovered that certain nerve cells were activated when the animal assumed a particular place in the environment. He could demonstrate that these “place cells” were not merely registering visual input, but were building up an inner map of the environment. O’Keefe concluded that the hippocampus generates numerous maps, represented by the collective activity of place cells that are activated in different environments. Therefore, the memory of an environment can be stored as a specific combination of place cell activities in the hippocampus.

May-Britt and Edvard Moser find the coordinates

May-Britt and Edvard Moser were mapping the connections to the hippocampus in rats moving in a room when they discovered an astonishing pattern of activity in a nearby part of the brain called the entorhinal cortex. Here, certain cells were activated when the rat passed multiple locations arranged in a hexagonal grid. Each of these cells was activated in a unique spatial pattern and collectively these “grid cells” constitute a coordinate system that allows for spatial navigation. Together with other cells of the entorhinal cortex that recognize the direction of the head and the border of the room, they form circuits with the place cells in the hippocampus. This circuitry constitutes a comprehensive positioning system, an inner GPS, in the brain.

A place for maps in the human brain

Recent investigations with brain imaging techniques, as well as studies of patients undergoing neurosurgery, have provided evidence that place and grid cells exist also in humans. In patients with Alzheimer´s disease, the hippocampus and entorhinal cortex are frequently affected at an early stage, and these individuals often lose their way and cannot recognize the environment. Knowledge about the brain´s positioning system may, therefore, help us understand the mechanism underpinning the devastating spatial memory loss that affects people with this disease.

The discovery of the brain’s positioning system represents a paradigm shift in our understanding of how ensembles of specialized cells work together to execute higher cognitive functions. It has opened new avenues for understanding other cognitive processes, such as memory, thinking and planning.

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Mimicking brain cells to boost computer memory power

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Researchers have brought ultra-fast, nano-scale data storage within striking reach, using technology that mimics the human brain.

Dr Sharath Sriram, RMIT University. Photo Credit: RMIT University

The researchers have built a novel nano-structure that offers a new platform for the development of highly stable and reliable nanoscale memory devices.

The pioneering work will feature on a forthcoming cover of prestigious materials science journal Advanced Functional Materials (11 November).

Project leader Dr Sharath Sriram, co-leader of the RMIT Functional Materials and Microsystems Research Group, said the nanometer-thin stacked structure was created using thin film, a functional oxide material more than 10,000 times thinner than a human hair.

“The thin film is specifically designed to have defects in its chemistry to demonstrate a ‘memristive’ effect – where the memory element’s behaviour is dependent on its past experiences,” Dr Sriram said.

“With flash memory rapidly approaching fundamental scaling limits, we need novel materials and architectures for creating the next generation of non-volatile memory.

“The structure we developed could be used for a range of electronic applications – from ultrafast memory devices that can be shrunk down to a few nanometers, to computer logic architectures that replicate the versatility and response time of a biological neural network.

“While more investigation needs to be done, our work advances the search for next generation memory technology can replicate the complex functions of human neural system – bringing us one step closer to the bionic brain.”

The research relies on memristors, touted as a transformational replacement for current hard drive technologies such as Flash, SSD and DRAM. Memristors have potential to be fashioned into non-volatile solid-state memory and offer building blocks for computing that could be trained to mimic synaptic interfaces in the human brain.

The research, which was supported by an Australian Research Council Discovery grant, was a collaboration between members of the Functional Materials and Microsystems Research Group and Professor Dmitri Strukov from the University of California, Santa Barbara.

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Stem Cell Discovery: Treatments for Blindness?

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Scientists at the University of Southampton have discovered that a region on the front surface of the eye harbours special stem cells that could treat blinding eye conditions.

This part of the eye is called the ‘corneal limbus’ and is a narrow gap lying between the transparent cornea and white sclera.

The research, published in PLOS ONE, showed that stem cells can be cultured from the corneal limbus in vitro. Under the correct culture conditions, these cells could be directed to behave like the cells needed to see light – photoreceptor cells.

The loss of photoreceptors cells causes irreversible blindness and researchers hope that this discovery could lead to new treatments for conditions such as age related macular degeneration, the leading cause of blindness in the developed world which affects around one in three people in the UK by age of 75.

Professor Andrew Lotery, of the University of Southampton and a Consultant Ophthalmologist at Southampton General Hospital led the study. He comments: “These cells are readily accessible, and they have surprising plasticity, which makes them an attractive cell resource for future therapies. This would help avoid complications with rejection or contamination because the cells taken from the eye would be returned to the same patient. More research is now needed to develop this approach before these cells are used in patients.”

Furthermore, these stem cells also exist in aged human eyes, and can be cultured even from the corneal limbus of 97 year olds. Therefore this discovery opens up the possibility of new treatments for the older generations, researchers believe.

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Scientists Erase Specific Memories in Mice

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Just look into the light: not quite, but researchers at the UC Davis Center for Neuroscience and Department of Psychology have used light to erase specific memories in mice, and proved a basic theory of how different parts of the brain work together to retrieve episodic memories.

During memory retrieval, cells in the hippocampus connect to cells in the brain cortex. Photo Credit: Photo illustration by Kazumasa Tanaka and Brian Wiltgen/UC Davis

Optogenetics, pioneered by Karl Diesseroth at Stanford University, is a new technique for manipulating and studying nerve cells using light. The techniques of optogenetics are rapidly becoming the standard method for investigating brain function.

Kazumasa Tanaka, Brian Wiltgen and colleagues at UC Davis applied the technique to test a long-standing idea about memory retrieval. For about 40 years, Wiltgen said, neuroscientists have theorized that retrieving episodic memories — memories about specific places and events — involves coordinated activity between the cerebral cortex and the hippocampus, a small structure deep in the brain.

“The theory is that learning involves processing in the cortex, and the hippocampus reproduces this pattern of activity during retrieval, allowing you to re-experience the event,” Wiltgen said. If the hippocampus is damaged, patients can lose decades of memories.

But this model has been difficult to test directly, until the arrival of optogenetics.

Wiltgen and Tanaka used mice genetically modified so that when nerve cells are activated, they both fluoresce green and express a protein that allows the cells to be switched off by light. They were therefore able both to follow exactly which nerve cells in the cortex and hippocampus were activated in learning and memory retrieval, and switch them off with light directed through a fiber-optic cable.

They trained the mice by placing them in a cage where they got a mild electric shock. Normally, mice placed in a new environment will nose around and explore. But when placed in a cage where they have previously received a shock, they freeze in place in a “fear response.”

Tanaka and Wiltgen first showed that they could label the cells involved in learning and demonstrate that they were reactivated during memory recall. Then they were able to switch off the specific nerve cells in the hippocampus, and show that the mice lost their memories of the unpleasant event. They were also able to show that turning off other cells in the hippocampus did not affect retrieval of that memory, and to follow fibers from the hippocampus to specific cells in the cortex.

“The cortex can’t do it alone, it needs input from the hippocampus,” Wiltgen said. “This has been a fundamental assumption in our field for a long time and Kazu’s data provides the first direct evidence that it is true.”

They could also see how the specific cells in the cortex were connected to the amygdala, a structure in the brain that is involved in emotion and in generating the freezing response.

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Prosthetic Hand: Amputees ‘Feel’ Sensations

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Even before he lost his right hand to an industrial accident 4 years ago, Igor Spetic had family open his medicine bottles. Cotton balls give him goose bumps.

Medical researchers are helping restore the sense of touch in amputees. Photo Credit: Image courtesy of Case Western Reserve University

Now, blindfolded during an experiment, he feels his arm hairs rise when a researcher brushes the back of his prosthetic hand with a cotton ball.

Spetic, of course, can’t feel the ball. But patterns of electric signals are sent by a computer into nerves in his arm and to his brain, which tells him different. “I knew immediately it was cotton,” he said.

That’s one of several types of sensation Spetic, of Madison, Ohio, can feel with the prosthetic system being developed by Case Western Reserve University and the Louis Stokes Cleveland Veterans Affairs Medical Center.

Spetic was excited just to “feel” again, and quickly received an unexpected benefit. The phantom pain he’d suffered, which he’s described as a vice crushing his closed fist, subsided almost completely. A second patient, who had less phantom pain after losing his right hand and much of his forearm in an accident, said his, too, is nearly gone.

Despite having phantom pain, both men said that the first time they were connected to the system and received the electrical stimulation, was the first time they’d felt their hands since their accidents. In the ensuing months, they began feeling sensations that were familiar and were able to control their prosthetic hands with more – well – dexterity.

“The sense of touch is one of the ways we interact with objects around us,” said Dustin Tyler, an associate professor of biomedical engineering at Case Western Reserve and director of the research. “Our goal is not just to restore function, but to build a reconnection to the world. This is long-lasting, chronic restoration of sensation over multiple points across the hand.”

“The work reactivates areas of the brain that produce the sense of touch, said Tyler, who is also associate director of the Advanced Platform Technology Center at the Cleveland VA. “When the hand is lost, the inputs that switched on these areas were lost.”

How the system works and the results will be published online in the journal Science Translational Medicine Oct. 8.

“The sense of touch actually gets better,” said Keith Vonderhuevel, of Sidney, Ohio, who lost his hand in 2005 and had the system implanted in January 2013. “They change things on the computer to change the sensation.

“One time,” he said, “it felt like water running across the back of my hand.”

The system, which is limited to the lab at this point, uses electrical stimulation to give the sense of feeling. But there are key differences from other reported efforts.

First, the nerves that used to relay the sense of touch to the brain are stimulated by contact points on cuffs that encircle major nerve bundles in the arm, not by electrodes inserted through the protective nerve membranes.

Surgeons Michael W Keith, MD and J. Robert Anderson, MD, from Case Western Reserve School of Medicine and Cleveland VA, implanted three electrode cuffs in Spetic’s forearm, enabling him to feel 19 distinct points; and two cuffs in Vonderhuevel’s upper arm, enabling him to feel 16 distinct locations.

Second, when they began the study, the sensation Spetic felt when a sensor was touched was a tingle. To provide more natural sensations, the research team has developed algorithms that convert the input from sensors taped to a patient’s hand into varying patterns and intensities of electrical signals. The sensors themselves aren’t sophisticated enough to discern textures, they detect only pressure.

The different signal patterns, passed through the cuffs, are read as different stimuli by the brain. The scientists continue to fine-tune the patterns, and Spetic and Vonderhuevel appear to be becoming more attuned to them.

Third, the system has worked for 2 ½ years in Spetic and 1½ in Vonderhueval. Other research has reported sensation lasting one month and, in some cases, the ability to feel began to fade over weeks.

A blindfolded Vonderhuevel has held grapes or cherries in his prosthetic hand—the signals enabling him to gauge how tightly he’s squeezing—and pulled out the stems.

“When the sensation’s on, it’s not too hard,” he said. “When it’s off, you make a lot of grape juice.”

Different signal patterns interpreted as sandpaper, a smooth surface and a ridged surface enabled a blindfolded Spetic to discern each as they were applied to his hand. And when researchers touched two different locations with two different textures at the same time, he could discern the type and location of each.

Tyler believes that everyone creates a map of sensations from their life history that enables them to correlate an input to a given sensation.

“I don’t presume the stimuli we’re giving is hitting the spots on the map exactly, but they’re familiar enough that the brain identifies what it is,” he said.

Because of Vonderheuval’s and Spetic’s continuing progress, Tyler is hopeful the method can lead to a lifetime of use. He’s optimistic his team can develop a system a patient could use at home, within five years.

In addition to hand prosthetics, Tyler believes the technology can be used to help those using prosthetic legs receive input from the ground and adjust to gravel or uneven surfaces. Beyond that, the neural interfacing and new stimulation techniques may be useful in controlling tremors, deep brain stimulation and more.

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The lab-grown penis: approaching a medical milestone

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After more than 20 years of research, a team of scientists are bioengineering penises in the lab which may soon be transplanted safely on to patients. It is an extraordinary medical endeavour that has implications for a wide range of disorders

Dr Anthony Atala: ‘We were completely stuck. We had no idea how to make this structure, let alone make it so it would perform like the natural organ.’

Penises grown in laboratories could soon be tested on men by scientists developing technology to help people with congenital abnormalities, or who have undergone surgery for aggressive cancer or suffered traumatic injury.

Researchers at the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina, are assessing engineered penises for safety, function and durability. They hope to receive approval from the US Food and Drug Administration and to move to human testing within five years.

Professor Anthony Atala, director of the institute, oversaw the team’s successful engineering of penises for rabbits in 2008. “The rabbit studies were very encouraging,” he said, “but to get approval for humans we need all the safety and quality assurance data, we need to show that the materials aren’t toxic, and we have to spell out the manufacturing process, step by step.”

The penises would be grown using a patient’s own cells to avoid the high risk of immunological rejection after organ transplantation from another individual. Cells taken from the remainder of the patient’s penis would be grown in culture for four to six weeks.

For the structure, they wash a donor penis in a mild detergent to remove all donor cells. After two weeks a collagen scaffold of the penis is left, on to which they seed the patient’s cultured cells – smooth muscle cells first, then endothelial cells, which line the blood vessels. Because the method uses a patient’s own penis-specific cells, the technology will not be suitable for female-to-male sex reassignment surgery.

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‘Endless possibilities’ for bio-nanotechnology

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Scientists from the University of Leeds have taken a crucial step forward in bio-nanotechnology, a field that uses biology to develop new tools for science, technology and medicine.

The new study, published in print today in the journal Nano Letters, demonstrates how stable ‘lipid membranes’ – the thin ‘skin’ that surrounds all biological cells – can be applied to synthetic surfaces.

Importantly, the new technique can use these lipid membranes to ‘draw’ – akin to using them like a biological ink – with a resolution of 6 nanometres (6 billionths of a meter), which is much smaller than scientists had previously thought was possible.

“This is smaller than the active elements of the most advanced silicon chips and promises the ability to position functional biological molecules – such as those involved in taste, smell, and other sensory roles – with high precision, to create novel hybrid bio-electronic devices,” said Professor Steve Evans, from the School of Physics and Astronomy at the University of Leeds and a co-author of the paper.

In the study, the researchers used something called Atomic Force Microscopy (AFM), which is an imaging process that has a resolution down to only a fraction of a nanometer and works by scanning an object with a miniscule mechanical probe. AFM, however, is more than just an imaging tool and can be used to manipulate materials in order to create nanostructures and to ‘draw’ substances onto nano-sized regions. The latter is called ‘nano-lithography’ and was the technique used by Professor Evans and his team in this research.

The ability to controllably ‘write’ and ‘position’ lipid membrane fragments with such high precision was achieved by Mr George Heath, a PhD student from the School of Physics and Astronomy at the University of Leeds and the lead author of the research paper.

Mr Heath said: “The method is much like the inking of a pen. However, instead of writing with fluid ink, we allow the lipid molecules – the ink – to dry on the tip first. This allows us to then write underwater, which is the natural environment for lipid membranes. Previously, other research teams have focused on writing with lipids in air and they have only been able to achieve a resolution of microns, which is a thousand times larger than what we have demonstrated. “

The research is of fundamental importance in helping scientists understand the structure of proteins that are found in lipid membranes, which are called ‘membrane proteins’. These proteins act to control what can be let into our cells, to remove unwanted materials, and a variety of other important functions.

For example, we smell things because of membrane proteins called ‘olfactory receptors’, which convert the detection of small molecules into electrical signals to stimulate our sense of smell. And many drugs work by targeting specific membrane proteins.

“Currently, scientists only know the structure of a small handful of membrane proteins. Our research paves the way to understand the structure of the thousands of different types of membrane proteins to allow the development of many new drugs and to aid our understanding of a range of diseases,” explained Professor Evans.

Aside from biological applications, this area of research could revolutionise renewable energy production.

Working in collaboration with researchers at the University of Sheffield, Professor Evans and his team have all of the membrane proteins required to construct a fully working mimic of the way plants capture sunlight. Eventually, the researchers will be able to arbitrarily swap out the biological units and replace them with synthetic components to create a new generation of solar cells.

Professor Evans concludes: “This is part of the emerging field of synthetic biology, whereby engineering principles are being applied to biological parts – whether it is for energy capture, or to create artificial noses for the early detection of disease or simply to advise you that the milk in your fridge has gone off.

“The possibilities are endless.”

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BGU ISREAL IGEM 2014 TEAM

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Ten BGU undergraduate students will represent Israel in the prestigiousiGEM (International Genetically Engineered Machine) competition for genetic engineering at MIT where they will compete against 250 other student teams from the top universities worldwide. The competition will be held November 1 – November 3, 2014 in Boston, MA.

The team, under the supervision of Prof. Smadar Cohen from the Avram and Stella Goldstein-Goren Department of Biotechnology Engineering is developing an innovative customized treatment for metabolic syndrome. The syndrome is diagnosed in one out of four people in the world’s population and includes symptoms such as diabetes and obesity, which are a significant catalyst for life-threatening heart disease.

Today, most of the traditional drugs against the syndrome cause unwanted side effects and only treat the symptoms. The team is working on developing “smart” drugs that are able to respond to body signals post injection and transform their operations in real time. These methods are expected to reduce side effects and improve the efficacy of treatment significantly. The treatment is carried out using biological and engineering methods that are at the forefront of cutting-edge science and are based on personalized treatment.

The team’s vision is to create a world in which synthetic biology and genetic engineering will be an integral part of medical treatment for everyone and their project is only the beginning of fulfilling their vision. The team is also working hard on integrating a healthy lifestyle (sports nutrition) and science in order to create a global awareness with an emphasis on technology and innovative research.

To that end, the team organized a special medical experts panel to present their project and cutting edge biological research. The well-known speakers came from various backgrounds such as: Diabetes specialists, personal-medicine physicians, nutritionists and more. The panel took place during the largest entrepreneurial conference in Israel, Innovation 2014, which drew over two thousand high-tech personnel, entrepreneurs, CEOs and other public figures.

This past Friday, the team organized a seminar day for 50 Bedouin students in medical professions, so they can become “Diabetes Ambassadors” to their communities. The event was sponsored by the Bengis Center for Entrepreneurship and Hi-Tech Management and in full collaboration with Dr. Yunis Abu-Rabia, a senior physician at Soroka University Medical Center who is an expert on Diabetes and was the first Bedouin doctor in the Negev. They are planning on organizing additional educational activities on synthetic biology and healthy living for the community.

The project is supported by the President of BGU, Prof. Rivka Carmi, The Rector of the University, Prof. Zvi HaCohen, Deans of the relevant Faculties, The Ministry of Science and Technology, The Ministry of Health and many companies.

The previous team from BGU (2013-iGEM BGU) that developed a “self-destruct” mechanism for bacteria was the first team from Israel to reach the world championships at MIT and won several awards such as silver medal, best presentation and more. They were even endorsed by Prime Minister Benjamin Netanyahu. This year, members of the BGU 2014 iGEM team are determined to reach first place, to bring honor to Israel and Ben-Gurion University, but more importantly, to help millions of patients around the world to improve their health and quality of life.

New approach to boosting biofuel production

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Yeast are commonly used to transform corn and other plant materials into biofuels such as ethanol. However, large concentrations of ethanol can be toxic to yeast, which has limited the production capacity of many yeast strains used in industry.

“Toxicity is probably the single most important problem in cost-effective biofuels production,” says Gregory Stephanopoulos, the Willard Henry Dow Professor of Chemical Engineering at MIT.

Now Stephanopoulos and colleagues at MIT and the Whitehead Institute for Biomedical Research have identified a new way to boost yeast tolerance to ethanol by simply altering the composition of the medium in which the yeast are grown. They report the findings, which they believe could have a significant impact on industrial biofuel production, in today’s issue of the journal Science.

Ethanol and other alcohols can disrupt yeast cell membranes, eventually killing the cells. The MIT team found that adding potassium and hydroxide ions to the medium in which yeast grow can help cells compensate for that membrane damage. By making these changes, the researchers were able to boost yeast’s ethanol production by about 80 percent. They also showed that this approach works with commercial yeast strains and other types of alcohols, including propanol and butanol, which are even more toxic to yeast.

“The more we understand about why a molecule is toxic, and methods that will make these organisms more tolerant, the more people will get ideas about how to attack other, more severe problems of toxicity,” says Stephanopoulos, one of the senior authors of the Science paper.

“This work goes a long way to squeezing the last drop of ethanol from sugar,” adds Gerald Fink, an MIT professor of biology, member of the Whitehead Institute, and the paper’s other senior author. Postdoc Felix Lam is the paper’s lead author, and graduate student Adel Ghaderi also contributed to the study.

Reinforcing cell defenses

The research team began this project searching for a gene or group of genes that could be manipulated to make yeast more tolerant to ethanol, but this approach did not yield much success. However, when the researchers began to experiment with altering the medium in which yeast grow, they found some dramatic results.

By augmenting the yeast’s environment with potassium chloride, and increasing the pH with potassium hydroxide, the researchers were able to dramatically boost ethanol production. They also found that these changes did not affect the biochemical pathway used by the yeast to produce ethanol: Yeast continued to produce ethanol at the same per-cell rate as long as they remained viable. Instead, the changes influenced their electrochemical membrane gradients — differences in ion concentrations inside and outside the membrane, which produce energy that the cell can harness to control the flow of various molecules into and out of the cell.

Ethanol increases the porosity of the cell membrane, making it very difficult for cells to maintain their electrochemical gradients. Increasing the potassium concentration and pH outside the cells helps them to strengthen the gradients and survive longer; the longer they survive, the more ethanol they make.

“By reinforcing these gradients, we’re energizing yeast to allow them to withstand harsher conditions and continue production. What’s also exciting to us is that this could apply beyond ethanol to more advanced biofuel alcohols that upset cell membranes in the same way,” Lam says.

The researchers found that they could also prolong survival, but not as much, by engineering the yeast cells to express more potassium and proton pumps, which are located in the cell membrane and pump potassium in and protons out.

Industrial relevance

Before yeast begin their work producing ethanol, the starting material, usually corn, must be broken down into

glucose. A significant feature of the new MIT study is that the researchers did their experiments at very high concentrations of glucose. While many studies have examined ways to boost ethanol tolerance at low glucose levels, the MIT team used concentrations of about 300 grams per liter, similar to what would be found in an industrial biofuel fermenter.

“If you really want to be relevant, you’ve got to go to these levels. Otherwise, what you learn at low ethanol levels is not likely to translate to industrial production,” Stephanopoulos says.

Lonnie Ingram, director of the Florida Center for Renewable Chemicals and Fuels at the University of Florida, describes the MIT team’s discovery as “remarkable and unexpected.”

“Few would have anticipated these results, which show that increasing electrochemical gradients across membranes provide a dramatic increase in alcohol tolerance,” Ingram says. “This discovery will have direct applications in commercial processes for alcohol production from high concentrations of sugar.”

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New drug-delivery capsule may replace injections

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Given a choice, most patients would prefer to take a drug orally instead of getting an injection. Unfortunately, many drugs, especially those made from large proteins, cannot be given as a pill because they get broken down in the stomach before they can be absorbed.

A schematic drawing of a microneedle pill with hollow needles. When the pill reaches the desired location in the digestive tract, the pH-sensitive coating surrounding the capsule dissolves, allowing the drug to be released through the microneedles. Photo Credit: Christine Daniloff/MIT, based on images by Carol Schoellhammer and Giovanni Traverso

To help overcome that obstacle, researchers at MIT and Massachusetts General Hospital (MGH) have devised a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed. In animal studies, the team found that the capsule delivered insulin more efficiently than injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

“This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug,” says Giovanni Traverso, a research fellow at MIT’s Koch Institute for Integrative Cancer Research, a gastroenterologist at MGH, and one of the lead authors of the paper, which appears in the Journal of Pharmaceutical Sciences.

Although the researchers tested their capsule with insulin, they anticipate that it would be most useful for delivering biopharmaceuticals such as antibodies, which are used to treat cancer and autoimmune disorders like arthritis and Crohn’s disease. This class of drugs, known as “biologics,” also includes vaccines, recombinant DNA, and RNA.

“The large size of these biologic drugs makes them nonabsorbable. And before they even would be absorbed, they’re degraded in your GI tract by acids and enzymes that just eat up the molecules and make them inactive,” says Carl Schoellhammer, a graduate student in chemical engineering and a lead author of the paper.

Safe and effective delivery

Scientists have tried designing microparticles and nanoparticles that can deliver biologics, but such particles are expensive to produce and require a new version to be engineered for each drug.

Schoellhammer, Traverso, and their colleagues set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the GI tract. Their prototype acrylic capsule, 2 centimeters long and 1 centimeter in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 millimeters long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the GI tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload. It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found that the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals’ blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.

“The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration,” Traverso says. “For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency.”

“This is a very interesting approach,” says Samir Mitragotri, a professor of chemical engineering at the University of California at Santa Barbara who was not involved in the research. “Oral delivery of drugs is a major challenge, especially for protein drugs. There is tremendous motivation on various fronts for finding other ways to deliver drugs without using the standard needle and syringe.”

Further optimization

This approach could also be used to administer vaccines that normally have to be injected, the researchers say.

The team now plans to modify the capsule so that peristalsis, or contractions of the digestive tract, would slowly squeeze the drug out of the capsule as it travels through the tract. They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

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