Tagged: Biology Toggle Comment Threads | Keyboard Shortcuts

  • richardmitnick 8:05 am on March 30, 2017 Permalink | Reply
    Tags: , Biology, , , , Ticks on the march   

    From NS: “Lyme disease is set to explode, and you can’t protect yourself” 

    NewScientist

    New Scientist

    29 March 2017
    Chelsea Whyte

    A new prediction says 2017 and 2018 will see major Lyme disease outbreaks in new areas. This could lead to lifelong health consequences, so where’s the vaccine?

    1
    Tick tock. Mike Peres/Custom Medical Stock Photo/SPL

    BY THE time he had finished his walk through the woods in New York state, Rick Ostfeld was ready to declare a public health emergency. He could read the warning signs in the acorns that littered the forest floor – seeds of a chain of events that will culminate in an unprecedented outbreak of Lyme disease this year.

    Since that day in 2015, Ostfeld has been publicising the coming outbreak. Thanks to a changing climate it could be one of the worst on record: the ticks that carry the disease have been found in places where it has never before been a problem – and where most people don’t know how to respond. The danger zone isn’t confined to the US: similar signs are flagging potential outbreaks in Europe. Polish researchers predict a major outbreak there in 2018.

    In theory, Ostfeld’s early warning system gives public health officials a two-year window to prepare. In many other cases, this would be enough time to roll out a vaccination programme. But there is no human vaccine for Lyme disease. Why not? And what can you do to protect yourself in the meantime?

    Lyme disease is the most common infection following an insect bite in the US: the Centers for Disease Control estimates that 300,000 Americans contract Lyme disease each year, calling it “a major US public health problem”. While it is easy enough to treat if caught early, we are still getting to grips with lifelong health problems that can stem from not catching it in time (see “Do I have Lyme disease?“).

    This is less of a problem when Lyme is confined to a few small areas of the US, but thanks in part to warmer winters, the disease is spreading beyond its usual territory, extending across the US (see map) and into Europe and forested areas of Asia. In Europe in particular, confirmed cases have been steadily rising for 30 years – today, the World Health Organization estimates that 65,000 people get Lyme disease each year in the region. In the UK, 2000 to 3000 cases are diagnosed each year, up tenfold from 2001, estimates the UK’s National Health Service.

    So how could a floor of acorns two years ago tell Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies in Millbrook, New York, that 2017 would see an outbreak of Lyme disease? It’s all down to what happens next.

    A bumper crop of the seeds – “like you were walking on ball bearings” – comes along every two to five years in Millbrook. Crucially, these nutrient-packed meals swell the mouse population: “2016 was a real mouse plague of a year,” he says. And mouse plagues bring tick plagues.

    Soon after hatching, young ticks start “questing” – grasping onto grasses or leaves with their hind legs and waving their forelegs, ready to hitch a ride on whatever passes by, usually a mouse.

    Gut reaction

    Once on board, the feast begins. Just one mouse can carry hundreds of immature ticks in their post-larval nymph stage.

    This is where the problems for us start. Mouse blood carries the Lyme-causing bacterium Borrelia burgdorferi, which passes to a tick’s gut as it feeds. The tick itself is unharmed, but each time it latches onto a new host to feed, the bacteria can move from its gut to the blood – including that of any human passers-by.

    “We predict the mice population based on the acorns and we predict infected nymph ticks with the mice numbers. Each step has a one year lag,” Ostfeld says.

    Ostfeld published his discovery of this chain of causation in 2006 [PLOS Biology]. Last year, researchers in Poland found the same trend there, with the same implications. “Last year we had a lot of oak acorns, so we might expect 2018 will pose a high risk of Lyme,” says Jakub Szymkowiak at Adam Mickiewicz University in Poznan, Poland.

    Those who live in traditional Lyme disease zones are well versed in tick awareness – wear long trousers in the woods, check yourself thoroughly afterwards, and more. But this advice will be less familiar in places that used to sit outside Lyme zones – like Poland. “That’s sort of the perfect storm,” says Ostfeld. “The public is unaware, so they’re not looking for it and they don’t get treated.”

    It’s not obvious when you have been bitten or infected: ticks are the size of a poppy seed, and not everyone gets the classic “bullseye” rash that is supposed to tip you off. The flu-like symptoms that follow are also easy to misdiagnose. And because antibodies to Lyme disease take a few weeks to develop, early tests can miss it. “That’s when you get late-stage, untreated, supremely problematic Lyme disease,” Ostfeld says.

    The best approach would be to vaccinate people at risk – but there is currently no vaccine. We used to have one, but thanks to anti-vaccination activists, that is no longer the case.

    In the late 1990s, a race was on to make the first Lyme disease vaccine. By December 1998, the US Food and Drug Administration approved the release of Lymerix, developed by SmithKline Beecham, now GSK. But the company voluntarily withdrew the drug after only four years.

    This followed a series of lawsuits – including one where recipients claimed Lymerix caused chronic arthritis. Influenced by now-discredited research purporting to show a link between the MMR vaccine and autism, activists raised the question of whether the Lyme disease vaccine could cause arthritis.

    Media coverage and the anti-Lyme-vaccination groups gave a voice to those who believed their pain was due to the vaccine, and public support for the vaccine declined. “The chronic arthritis was not associated with Lyme,” says Stanley Plotkin, an adviser to pharmaceutical company Sanofi Pasteur. “When you’re dealing with adults, all kinds of things happen to them. They get arthritis, they get strokes, heart attacks. So unless you have a control group, you’re in la-la land.”

    But there was a control group – the rest of the US population. And when the FDA reviewed the vaccine’s adverse event reports in a retrospective study, they found only 905 reports for 1.4 million doses. Still, the damage was done, and the vaccine was benched.

    After that, “no one touched it”, says Thomas Lingelbach, CEO at Valneva, a biotech company based in France. Until now: Valneva has a vaccine in early human trials. It will improve on Lymerix, acting against all five strains of the disease instead of just the one most common in the US, and it will be suitable for children.

    Lingelbach knows the battles his firm will face. “It will be hard to convince anti-vax lobbyists,” he says. That fight is still some way off: any public roll-out is at least six years away.

    What makes this wait especially galling for some is that there is a vaccine for your pet. “It’s ironic that you can vaccinate your animal and you can’t vaccinate yourself,” Plotkin says.

    In the animal vaccine, instead of exposing Fido to a weakened version of the antigen to trigger antibodies, it works within the tick, neutralising B. burgdorferi by altering the expression of a protein on the bacterium before it enters the bloodstream. This is how a human version would work. “The underlying scientific principle is not very far away from what it is in the veterinary environment,” says Lingelbach.

    Some people have suggested taking the animal vaccine, but Plotkin doesn’t recommend this as it hasn’t been tested in people so there is insufficient safety data. “You just don’t have classical efficacy data in humans,” he says. It is also illegal in the US and UK for vets to practise medicine on humans.

    While we wait for a human vaccine, you might start keeping track of your local acorn populations – but brush up on your anti-tick measures before you hit the woods.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

     
  • richardmitnick 11:05 am on March 24, 2017 Permalink | Reply
    Tags: , , Biology, , nicotinamide adenine dinucleotide (NAD+)   

    From COSMOS: “Can ageing be held at bay by injections and pills?” 

    Cosmos Magazine bloc

    COSMOS

    24 March 2017
    Elizabeth Finkel

    1
    Two fast ageing mice. The one on the left was treated with a FOXO4 peptide, which targets senescent cells and leads to hair regrowth in 10 days.
    Peter L.J. de Keizer

    The day we pop up a pill or get a jab to stave off ageing is closer, thanks to two high profile papers just published today.

    A Science paper from a team, led by David Sinclair from Harvard Medical School and the University of NSW, shows how popping a pill that raises the levels of a natural molecule called nicotinamide adenine dinucleotide (NAD+) staves off the DNA damage that leads to aging.

    The other paper, published in Cell, led by Peter de Keizer’s group at Erasmus University in the Netherlands, shows how a short course of injections to kill off defunct “senescent cells” reversed kidney damage, hair loss and muscle weakness in aged mice.

    Taken together, the two reports give a glimpse of how future medications might work together to forestall ageing when we are young, and delete damaged cells as we grow old. “This is what we in the field are planning”, says Sinclair.

    Sinclair has been searching for factors that might slow the clock of ageing for decades. His group stumbled upon the remarkable effects of NAD+ in the course of studying powerful anti-ageing molecules known as sirtuins, a family of seven proteins that mastermind a suite of anti-ageing mechanisms, including protecting DNA and proteins.

    Resveratrol, a compound found in red wine, stimulates their activity. But back in 2000, Sinclair’s then boss Lenny Guarente at MIT discovered a far more powerful activator of sirtuins – NAD+. It was a big surprise.

    “It would have to be the most boring molecule in the world”, notes Sinclair.

    It was regarded as so common and boring that no-one thought it could play a role in something as profound as tweaking the ageing clock. But Sinclair found that NAD+ levels decline with age.

    “By the time you’re 50, the levels are halved,” he notes.

    And in 2013, his group showed [Cell] that raising NAD+ levels in old mice restored the performance of their cellular power plants, mitochondria.

    One of the key findings of the Science paper is identifying the mechanism by which NAD+ improves the ability to repair DNA. It acts like a basketball defence, staying on the back of a troublesome protein called DBC1 to keep it away from the key player PARP1– a protein that repairs DNA.

    When NAD+ levels fall, DBC1 tackles PARP1. End result: DNA damage goes unrepaired and the cell ‘ages’.

    “We ‘ve discovered the reason why DNA repair declines as we get older. After 100 years that’s exciting,” says Sinclair .

    His group has helped developed a compound, nicotinamide mono nucleotide (NMN), that raises NAD+ levels. As reported in the Science paper, when injected into aged mice it restored the ability of their liver cells to repair DNA damage. In young mice that had been exposed to DNA-damaging radiation, it also boosted their ability to repair it. The effects were seen within a week of the injection.

    These kinds of results have impressed NASA. The organisation is looking for methods to protect its astronauts from radiation damage during their one-year trip to Mars. Last December it hosted a competition for the best method of preventing that damage. Out of 300 entries, Sinclair’s group won.

    As well as astronauts, children who have undergone radiation therapy for cancer might also benefit from this treatment. According to Sinclair, clinical trials for NMN should begin in six months. While many claims have been made for NAD+ to date, and compounds are being sold to raise its levels, this will be the first clinical trial, says Sinclair.

    By boosting rates of DNA repair, Sinclair’s drug holds the hope of slowing down the ageing process itself. The work from de Keizer’s lab, however, offers the hope of reversing age-related damage.

    His approach stems from exploring the role of senescent cells. Until 2001, these cells were not really on the radar of researchers who study ageing. They were considered part of a protective mechanism that mothballs damaged cells, preventing them from ever multiplying into cancer cells.

    The classic example of senescent cells is a mole. These pigmented skin cells have incurred DNA damage, usually triggering dangerous cancer-causing genes. To keep them out of action, the cells are shut down.

    If humans lived only the 50-year lifespan they were designed for, there’d be no problem. But because we exceed our use-by date, senescent cells end up doing harm.

    As Judith Campisi at the Buck Institute, California, showed in 2001, they secrete inflammatory factors that appear to age the tissues around them.

    But cells have another option. They can self-destruct in a process dubbed apoptosis. It’s quick and clean, and there are no nasty compounds to deal with.

    So what relegates some cells to one fate over another? That’s the question Peter de Keizer set out to solve when he did a post-doc in Campisi’s lab back in 2009.

    Finding the answer didn’t take all that long. A crucial protein called p53 was known to give the order for the coup de grace. But sometimes it showed clemency, relegating the cell to senesce instead.

    De Keizer used sensitive new techniques to identify that in senescent cells, it was a protein called FOXO4 that tackled p53, preventing it from giving the execution order.

    The solution was to interfere with this liaison. But it’s not easy to wedge proteins apart; not something that small diffusible molecules – the kind that make great drugs – can do.

    De Keizer, who admits to “being stubborn” was undaunted. He began developing a protein fragment that might act as a wedge. It resembled part of the normal FOXO4 protein, but instead of being built from normal L- amino acids it was built from D-amino acids. It proved to be a very powerful wedge.

    Meanwhile other researchers were beginning to show that executing senescent cells was indeed a powerful anti-ageing strategy. For instance, a group from the Mayo Clinic last year showed that mice genetically engineered to destroy 50-70% of their senescent cells in response to a drug experienced a greater “health span”.

    Compared to their peers they were more lively and showed less damage to their kidney and heart muscle. Their average lifespan was also boosted by 20%.

    But humans are not likely to undergo mass genetic engineering. To achieve similar benefits requires a drug that works on its own. Now de Keizer’s peptide looks like it could be the answer.

    As the paper in Cell shows, in aged mice, three injections of the peptide per week had dramatic effects. After three weeks, the aged balding mice regrew hair and showed improvements to kidney function. And while untreated aged mice could be left to flop onto the lab bench while the technician went for coffee, treated mice would scurry away.

    “It’s remarkable. it’s the best result I’ve seen in age reversal,” says Sinclair of his erstwhile competitor’s paper.

    Dollops of scepticism are healthy when it comes to claims of a fountain of youth – even de Keizer admits his work “sounds too good to be true”. Nevertheless some wary experts are impressed.

    “It raises my optimism that in our lifetime we will see treatments that can ameliorate multiple age-related diseases”, says Campisi.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

     
  • richardmitnick 10:53 am on March 24, 2017 Permalink | Reply
    Tags: , Biology, , Fight looms over evolution's essence, Palaeontologogy, Species selection   

    From COSMOS: “Macro or micro? Fight looms over evolution’s essence” 

    Cosmos Magazine bloc

    COSMOS

    24 March 2017
    Stephen Fleischfresser

    1
    Evolution over deep time: is it in the genes, or the species?
    Roger Harris/Science Photo Library

    A new paper threatens to pit palaeontologists against the rest of the biological community and promises to reignite the often-prickly debate over the question of the level at which selection operates.

    Carl Simpson, a researcher in palaeobiology at the Smithsonian Institution National Museum of Natural History, has revived the controversial idea of ‘species selection’: that selective forces in nature operate on whole species at a macroevolutionary scale, rather than on individuals at the microevolutionary level.

    Macroevolution, mostly concerned with extinct species, is the study of large-scale evolutionary phenomena across vast time spans. By contrast, microevolution focusses on evolution in individuals and species over shorter periods, and is the realm of biologists concerned with living organisms, sometimes called neontologists.

    Neontologists, overall, maintain that all evolutionary phenomena can be explained in microevolutionary terms. Macroevolutionists often disagree.

    In a paper, yet to be peer-reviewed, on the biological pre-print repository bioRxiv, Simpson has outlined a renewed case for species selection, using recent research and new insights, both scientific and philosophical. And this might be too much for the biological community to swallow.

    The debate over levels of selection dates to Charles Darwin himself and concerns the question of what the ‘unit of selection’ is in evolutionary biology.

    The default assumption is that the individual organism is the unit of selection. If individuals of a particular species possess a trait that gives them reproductive advantage over others, then these individuals will have more offspring.

    If this trait is heritable, the offspring too will reproduce at a higher rate than other members of the species. With time, this leads to the advantageous trait becoming species-typical.

    Here, selection is operating on individuals, and this percolates up to cause species-level characteristics.

    While Darwin favoured this model, he recognised that certain biological phenomena, such as the sterility of workers in eusocial insects such as bees and ants, could best be explained if selection operated at a group level.

    Since Darwin, scientists have posited different units of selection: genes, organelles, cells, colonies, groups and species among them.

    Simpson’s argument hinges on the kind of macroevolutionary phenomena common in palaeontology: speciation and extinction over deep-time. Species selection is real, he says, and is defined as, “a macroevolutionary analogue of natural selection, with species playing an analogous part akin to that played by organisms in microevolution”.

    Simpson takes issue with the argument that microevolutionary processes such as individual selection percolate up to cause macroevolutionary phenomena.

    He presents evidence contradicting the idea, and concludes that the “macroevolutionary patterns we actually observe are not simply the accumulation of microevolutionary change… macroevolution occurs by changes within a population of species.”

    How this paper will be received, only time will tell. A 2010 paper in Nature saw the famous evolutionary biologist E. O. Wilson recant decades of commitment to the gene as the unit of selection, hinting instead at group selection. The mere suggestion of this brought a sharp rebuke from 137 scientists.

    Simpson’s claim is more radical again, so we can only wait for the controversy to deepen.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

     
  • richardmitnick 10:14 am on March 16, 2017 Permalink | Reply
    Tags: , Biology, , , Deep-sea corals, Desmophyllum dianthus, , Study: Cold Climates and Ocean Carbon Sequestration, Why the earth goes through periodic climate change   

    From Caltech: “Study: Cold Climates and Ocean Carbon Sequestration” 

    Caltech Logo

    Caltech

    03/14/2017

    Robert Perkins
    (626) 395-1862
    rperkins@caltech.edu

    1
    Tony Wang (left) and Jess Adkins (right) with samples of Desmophyllum dianthus fossils.

    Deep-sea corals reveal why atmospheric carbon was reduced during colder time periods

    We know a lot about how carbon dioxide (CO2) levels can drive climate change, but how about the way that climate change can cause fluctuations in CO2 levels? New research from an international team of scientists reveals one of the mechanisms by which a colder climate was accompanied by depleted atmospheric CO2 during past ice ages.

    The overall goal of the work is to better understand how and why the earth goes through periodic climate change, which could shed light on how man-made factors could affect the global climate.

    Earth’s average temperature has naturally fluctuated by about 4 to 5 degrees Celsius over the course of the past million years as the planet has cycled in and out of glacial periods. During that time, the earth’s atmospheric CO2 levels have fluctuated between roughly 180 and 280 parts per million (ppm) every 100,000 years or so. (In recent years, man-made carbon emissions have boosted that concentration up to over 400 ppm.)

    About 10 years ago, researchers noticed a close correspondence between the fluctuations in CO2 levels and in temperature over the last million years. When the earth is at its coldest, the amount of CO2 in the atmosphere is also at its lowest. During the most recent ice age, which ended about 11,000 years ago, global temperatures were 5 degrees Celsius lower than they are today, and atmospheric CO2 concentrations were at 180 ppm.

    Using a library of more than 10,000 deep-sea corals collected by Caltech’s Jess Adkins, an international team of scientists has shown that periods of colder climates are associated with higher phytoplankton efficiency and a reduction in nutrients in the surface of the Southern Ocean (the ocean surrounding the Antarctic), which is related to an increase in carbon sequestration in the deep ocean. A paper about their research appears the week of March 13 in the online edition of the Proceedings of the National Academy of Sciences.

    “It is critical to understand why atmospheric CO2 concentration was lower during the ice ages. This will help us understand how the ocean will respond to ongoing anthropogenic CO2 emissions,” says Xingchen (Tony) Wang, lead author of the study. Wang was a graduate student at Princeton while conducting the research in the lab of Daniel Sigman, Dusenbury Professor of Geological and Geophysical Sciences. He is now a Simons Foundation Postdoctoral Fellow on the Origins of Life at Caltech.

    There is 60 times more carbon in the ocean than in the atmosphere—partly because the ocean is so big. The mass of the world’s oceans is roughly 270 times greater than that of the atmosphere. As such, the ocean is the greatest regulator of carbon in the atmosphere, acting as both a sink and a source for atmospheric CO2.

    Biological processes are the main driver of CO2 absorption from the atmosphere to the ocean. Just like photosynthesizing trees and plants on land, plankton at the surface of the sea turn CO2 into sugars that are eventually consumed by other creatures. As the sea creatures who consume those sugars—and the carbon they contain—die, they sink to the deep ocean, where the carbon is locked away from the atmosphere for a long time. This process is called the “biological pump.”

    A healthy population of phytoplankton helps lock away carbon from the atmosphere. In order to thrive, phytoplankton need nutrients—notably, nitrogen, phosphorus, and iron. In most parts of the modern ocean, phytoplankton deplete all of the available nutrients in the surface ocean, and the biological pump operates at maximum efficiency.

    However, in the modern Southern Ocean, there is a limited amount of iron—which means that there are not enough phytoplankton to fully consume the nitrogen and phosphorus in the surface waters. When there is less living biomass, there is also less that can die and sink to the bottom—which results in a decrease in carbon sequestration. The biological pump is not currently operating as efficiently as it theoretically could.

    To track the efficiency of the biological pump over the span of the past 40,000 years, Adkins and his colleagues collected more than 10,000 fossils of the coral Desmophyllum dianthus.

    Why coral? Two reasons: first, as it grows, coral accretes a skeleton around itself, precipitating calcium carbonate (CaCO3) and other trace elements (including nitrogen) out of the water around it. That process creates a rocky record of the chemistry of the ocean. Second, coral can be precisely dated using a combination of radiocarbon and uranium dating.

    “Finding a few centimeter-tall fossil corals 2,000 meters deep in the ocean is no trivial task,” says Adkins, Smits Family Professor of Geochemistry and Global Environmental Science at Caltech.

    Adkins and his colleagues collected coral from the relatively narrow (500-mile) gap known as the Drake Passage between South America and Antarctica (among other places). Because the Southern Ocean flows around Antarctica, all of its waters funnel through that gap—making the samples Adkins collected a robust record of the water throughout the Southern Ocean.

    Wang analyzed the ratios of two isotopes of nitrogen atoms in these corals – nitrogen-14 (14N, the most common variety of the atom, with seven protons and seven neutrons in its nucleus) and nitrogen-15 (15N, which has an extra neutron). When phytoplankton consume nitrogen, they prefer 14N to 15N. As a result, there is a correlation between the ratio of nitrogen isotopes in sinking organic matter (which the corals then eat as it falls to the seafloor) and how much nitrogen is being consumed in the surface ocean—and, by extension, the efficiency of the biological pump.

    A higher amount of 15N in the fossils indicates that the biological pump was operating more efficiently at that time. An analogy would be monitoring what a person eats in their home. If they are eating more of their less-liked foods, then one could assume that the amount of food in their pantry is running low.

    Indeed, Wang found that higher amounts of 15N were present in fossils corresponding to the last ice age, indicating that the biological pump was operating more efficiently during that time. As such, the evidence suggests that colder climates allow more biomass to grow in the surface Southern Ocean—likely because colder climates experience stronger winds, which can blow more iron into the Southern Ocean from the continents. That biomass consumes carbon, then dies and sinks, locking it away from the atmosphere.

    Adkins and his colleagues plan to continue probing the coral library for further details about the cycles of ocean chemistry changes over the past several hundred thousand years.

    The study is titled “Deep-sea coral evidence for lower Southern Ocean surface nitrate concentrations during the last ice age.” Coauthors include scientists from Caltech, Princeton University, Pomona College, the Max Planck Institute for Chemistry in Germany, University of Bristol, and ETH Zurich in Switzerland. This research was funded by the National Science Foundation, Princeton University, the European Research Council, and the Natural Environment Research Council.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
    Caltech buildings

     
  • richardmitnick 9:23 am on March 8, 2017 Permalink | Reply
    Tags: , Biology, , cure cancer, , , Push button,   

    From Paulson: Women in STEM – “Push button, cure cancer” Ph.D. candidates Nabiha Saklayen and Marinna Madrid 

    Harvard School of Engineering and Applied Sciences
    John A Paulson School of Engineering and Applied Sciences

    March 7, 2017
    Adam Zewe

    Two Harvard graduate students want to make curing blood cancer or HIV as easy as pressing a button.

    2
    Saklayen and Madrid are excited to move forward with their startup, Cellino. (Photo by Adam Zewe/SEAS Communications)

    1
    Cellino is a spinoff of the nanotechnology research being conducted in the Mazur lab. (Photo by Adam Zewe/SEAS Communications)

    Ph.D. candidates Nabiha Saklayen and Marinna Madrid have launched a startup to develop a simple, push-button device clinicians could use for gene therapy treatments. Their enterprise, Cellino, hopes to commercialize technology being developed in the lab of Eric Mazur, Balkanski Professor of Physics and Applied Physics at the John A. Paulson School of Engineering and Applied Sciences.

    The early-stage laboratory spinoff, which the pair launched in November, claimed first prize in the International Society for Optics and Photonics (SPIE) Startup Challenge, a pitch-off contest between more than 40 startups from around the world. In addition to winning $10,000 cash and $5,000 in optics products, Saklayen and Madrid were lauded for the impressive business potential of their startup.

    Their technique uses laser-activated nanostructures to deliver gene therapies directly into cells. When a laser is shined onto the nanostructures, the intense hot spots can open transient pores in nearby cells, Saklayen explained.

    “These pores are open long enough for any cargo that is around in the surrounding liquid to diffuse into the cell, and then the pores seal,” she said. “It is sort of like a magical opening where we can deliver molecules into the cell without damaging it, in a very targeted, quick way.”

    Developing effective intracellular delivery methods is a problem that has plagued biologists for decades, partly because the plasma membrane that surrounds a cell is selectively permeable and bars most molecules from entering.

    “Biologists have tried a number of different methods to do this, including viruses and chemical and physical processes, but none of them have been consistent enough and safe enough to be used reliably in treatments for blood disease,” said Madrid.

    The reliability of the nanostructure method developed at SEAS would give it a leg up over current practices. The biggest hurdle Madrid and Saklayen face now is translating the Mazur lab’s technology into a scalable, turnkey device.

    Their goal is to package the technology into a shoebox-sized device that contains everything a user needs—the laser, substrates, optical components, and computer interface. A user would put a patient’s cells and the nanofabricated chips into the device and use a touch screen to treat the cells, which could then be implanted into the patient.

    According to the Cellino team, those cells could be used to treat a number of different blood diseases, including HIV and blood cancers. By delivering gene-editing molecules into a patient’s hematopoietic stem cells, for instance, a clinician could repopulate a patient’s bone marrow with HIV-resistant cells. To treat cancers that affect the blood, the technology could be used to weaponize a patient’s T-cells, and then return them to the blood stream to attack the cancer.

    “What I find really exciting about this project is it is really pushing the barriers of what is the norm,” Saklayen said. “People talk about curing blood cancer all the time, but we have this unique opportunity to really enable that. That is the most inspiring part—we have an opportunity to make a difference in people’s lives. That is what drives me everyday to keep working hard.”

    As they move forward with Cellino, Saklayen and Madrid are working closely with Harvard’s Office of Technology Development (OTD), which has filed patent applications to secure the lab’s intellectual property and develop a viable commercialization strategy for the technology. Alan Gordon, a Director of Business Development in OTD, has been advising the team on how to develop a business plan and launch the company.

    After graduating from the Ph.D. program this spring, Saklayen will pursue Cellino full time. Madrid plans to graduate early so she can soon focus solely on the company, too. The co-founders have applied to a number of startup incubators and plan to enter additional pitch competitions to gain more validation for both their technology and their business plan.

    “There is definitely a production challenge when you talk about making things at a larger scale, but we are making good progress,” Madrid said. “The technology is very powerful because it is so streamlined. Now it is all about packaging.”

    Mazur is proud of his students’ accomplishments and excited for the potential of their startup. “This work is really transformative and opens the door to new therapies for currently incurable diseases,” he said.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Through research and scholarship, the Harvard School of Engineering and Applied Sciences (SEAS) will create collaborative bridges across Harvard and educate the next generation of global leaders. By harnessing the power of engineering and applied sciences we will address the greatest challenges facing our society.

    Specifically, that means that SEAS will provide to all Harvard College students an introduction to and familiarity with engineering and technology as this is essential knowledge in the 21st century.

    Moreover, our concentrators will be immersed in the liberal arts environment and be able to understand the societal context for their problem solving, capable of working seamlessly withothers, including those in the arts, the sciences, and the professional schools. They will focus on the fundamental engineering and applied science disciplines for the 21st century; as we will not teach legacy 20th century engineering disciplines.

    Instead, our curriculum will be rigorous but inviting to students, and be infused with active learning, interdisciplinary research, entrepreneurship and engineering design experiences. For our concentrators and graduate students, we will educate “T-shaped” individuals – with depth in one discipline but capable of working seamlessly with others, including arts, humanities, natural science and social science.

    To address current and future societal challenges, knowledge from fundamental science, art, and the humanities must all be linked through the application of engineering principles with the professions of law, medicine, public policy, design and business practice.

    In other words, solving important issues requires a multidisciplinary approach.

    With the combined strengths of SEAS, the Faculty of Arts and Sciences, and the professional schools, Harvard is ideally positioned to both broadly educate the next generation of leaders who understand the complexities of technology and society and to use its intellectual resources and innovative thinking to meet the challenges of the 21st century.

    Ultimately, we will provide to our graduates a rigorous quantitative liberal arts education that is an excellent launching point for any career and profession.

     
  • richardmitnick 10:44 am on March 6, 2017 Permalink | Reply
    Tags: , Biology, , Metabolism matters, Somites   

    From EMBL: “Metabolism matters” 

    EMBL European Molecular Biology Laboratory bloc

    European Molecular Biology Laboratory

    2 March 2017
    Sonia Furtado Neves

    1
    Scientists can now study glycolysis in embryos, thanks to the EMBL scientists’ pyruvate sensor. IMAGE: Vinay Bulusu/EMBL

    Cells at different stages of differentiation get energy in different ways, a new approach developed at EMBL shows.

    Life requires energy. The strategy a cell uses to obtain that energy can influence not only how fast it multiplies but also a variety of other processes, like which of its genes are turned on. This process – called metabolism – is challenging to track in time and space, so it has not been studied much in developing embryos. Alexander Aulehla shares how, in work published this week in Developmental Cell, his lab is starting to fill that gap.

    What did you find?

    To study energy metabolism during development, we looked at how somites – the parts of the embryo that will eventually give rise to the vertebral column and striated muscles – are formed in the mouse embryo. Somites develop from presomitic mesoderm (PSM). But cells in the PSM don’t all become somite cells at once. The tail bud, at one end of the PSM, contains cells that are still in a stem-cell-like state, while at the other end, cells are differentiating into somites.

    We found that cells at different points of the PSM generate energy in different ways. Undifferentiated cells in the tail bud showed a higher rate of glycolysis – they get their energy mainly by breaking down glucose. In contrast, cells that are about to differentiate had a higher rate of respiration. And there’s a gradient between these two extremes, with more glycolysis the closer you get to the tail bud.

    2
    The sensor developed by the EMBL scientists changes colour when cells have higher pyruvate levels (right). IMAGE: Vinay Bulusu/EMBL

    How did you do it?

    This is one of those projects that was really only possible at EMBL. Vinay Bulusu had an EMBL Interdisciplinary Postdoc fellowship (EIPOD) to work in my lab and Carsten Schultz’s lab. That allowed us to say “let’s try something quite daring: can we visualise pyruvate (an important product of glycolysis) in a mouse embryo?” Working with the Schultz lab, Vinay was able to design a sensor (called a FRET sensor) that measures the amount of pyruvate, not just in cells in a dish, but in an embryo. Then we created a transgenic mouse line that expresses that FRET sensor in all cells and used those mice to analyse pyruvate levels during PSM development using real-time imaging. Thanks to a collaboration with Uwe Sauer’s lab at ETH Zurich, we were also able to use mass spectrometry to directly measure other products of glycolysis, to confirm that there’s a higher rate of glycolysis in the tail bud. It will be exciting to see how others can now use the FRET sensor mouse line in different contexts.

    What questions does this raise?

    The main question this raises is ‘why?’ Why do PSM cells, which all seem to proliferate at a similar rate, get energy in different ways? We have evidence this could be linked to – and even influence – the signaling machineries that control differentiation. A companion study published alongside ours confirms this link and we are now investigating exactly how this happens at the molecular level.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    EMSL campus

    EMBL is Europe’s flagship laboratory for the life sciences, with more than 80 independent groups covering the spectrum of molecular biology. EMBL is international, innovative and interdisciplinary – its 1800 employees, from many nations, operate across five sites: the main laboratory in Heidelberg, and outstations in Grenoble; Hamburg; Hinxton, near Cambridge (the European Bioinformatics Institute), and Monterotondo, near Rome. Founded in 1974, EMBL is an inter-governmental organisation funded by public research monies from its member states. The cornerstones of EMBL’s mission are: to perform basic research in molecular biology; to train scientists, students and visitors at all levels; to offer vital services to scientists in the member states; to develop new instruments and methods in the life sciences and actively engage in technology transfer activities, and to integrate European life science research. Around 200 students are enrolled in EMBL’s International PhD programme. Additionally, the Laboratory offers a platform for dialogue with the general public through various science communication activities such as lecture series, visitor programmes and the dissemination of scientific achievements.

     
  • richardmitnick 11:33 am on March 5, 2017 Permalink | Reply
    Tags: , , Biology, Biotechnology, , , Hamilton Smith, , Methylation, Restriction enzyme, The Man Who Kicked Off the Biotech Revolution   

    From Nautilus: “The Man Who Kicked Off the Biotech Revolution” Hamilton Smith 

    Nautilus

    Nautilus

    3.5.17
    Carl Zimmer

    It’s hard to tell precisely how big a role biotechnology plays in our economy, because it infiltrates so many parts of it. Genetically modified organisms such as microbes and plants now create medicine, food, fuel, and even fabrics. Recently, Robert Carlson, of the biotech firm Biodesic and the investment firm Bioeconomy Capital, decided to run the numbers and ended up with an eye-popping estimate. He concluded that in 2012, the last year for which good data are available, revenues from biotechnology in the United States alone were over $324 billion.

    “If we talk about mining or several manufacturing sectors, biotech is bigger than those,” said Carlson. “I don’t think people appreciate that.”

    1
    Matchmaker Biotech pioneer Hamilton Smith chose to study recombination in a species of bacteria called Haemophilus influenza (above), which can take up foreign DNA fragments and integrate them into its own DNA. Media for Medical/UIG via Getty Images

    What makes the scope of biotech so staggering is not just its size, but its youth. Manufacturing first exploded in the Industrial Revolution of the 19th century. But biotech is only about 40 years old. It burst into existence thanks largely to a discovery made in the late 1960s by Hamilton Smith, a microbiologist then at Johns Hopkins University, and his colleagues, that a protein called a restriction enzyme can slice DNA. Once Smith showed the world how restriction enzymes work, other scientists began using them as tools to alter genes.

    “And once you have the ability to start to manipulate the world with those tools,” said Carlson, “the world opens up.”

    The story of restriction enzymes is a textbook example of how basic research can ultimately have a huge impact on society. Smith had no such grand ambitions when he started his work. He just wanted to do some science. “I was just having a lot of fun, learning as I went,” Smith, now 85, said.

    In 1968, when Smith was a new assistant professor at Johns Hopkins University, he became curious about how cells cut DNA into pieces and shuffle them into new arrangements—a process known as recombination. “It’s a universal thing,” Smith said. “Every living thing has recombination systems. But at the time, no one was sure how it worked, mechanically.”

    Smith chose to study recombination in a species of bacteria called Haemophilus influenza. Like many other species, H. influenzae can take up foreign DNA, either sucking in loose fragments from the environment or gaining them from microbial donors. Somehow, the bacterium can then integrate these fragments into its own DNA.

    Bacteria gain useful genes in this way, endowing them with new traits such as resistance to antibiotics. But recombination also has a dark side for H. influenzae. Invading viruses can hijack the recombination machinery in bacteria. They then insert their own genes into their host’s DNA, so that the microbes make new copies of the virus.

    To understand recombination, Smith produced radioactive viruses by introducing viruses into bacteria that had been fed radioactive phosphorus. New viruses produced inside the bacteria ended up with radioactive phosphorus in their DNA. Smith and his colleagues could then unleash these radioactive viruses on other bacteria. The scientists expected that during the infection, the bacteria’s genes would become radioactive as the viruses inserted their genetic material into their host’s DNA.

    At least that was they thought would happen. When Smith’s graduate student Kent Wilcox infected bacteria with the radioactive viruses, the radioactivity never ended up in the bacteria’s own genome.

    Trying to make sense of the failure, Wilcox suggested to Smith that the bacteria were destroying the viral DNA. He based his suggestion on a hypothesis proposed a few years earlier by Werner Arber, a microbiologist at the University of Geneva. Arber speculated that enzymes could restrict the growth of viruses by chopping up their DNA, and dubbed these hypothetical molecules “restriction enzymes.”

    Arber recognized that if restriction enzymes went on an unchecked rampage, they could kill the bacteria themselves by chopping up their own DNA. He speculated that bacteria were shielding their own DNA from assault, and thus avoiding suicide, by covering their genes with carbon and hydrogen atoms—a process known as methylation. The restriction enzymes couldn’t attack methylated DNA, Arber proposed, but it could attack the unprotected DNA of invading viruses.

    The week before Wilcox had carried out his baffling experiment, Smith had assigned his lab a provocative new paper supporting Arber’s hypothesis. Matthew Meselson and Robert Yuan at Harvard University reported in the paper how they had discovered a protein in E. coli that cut up foreign DNA—in other words, an actual restriction enzyme. With that paper fresh in his mind, Wilcox suggested to Smith that they had just stumbled across another restriction enzyme in Haemophilus influenzae.

    Smith tested the idea with an elegant experiment. He poured viral DNA into a test tube, and DNA from H. influenza into another. To each of these tubes, he then added a soup of proteins from the bacteria. If indeed the bacteria made restriction enzymes, the enzymes in the soup would chop up the viral DNA into small pieces.

    Scientists were decades away from inventing the powerful sequencers that are used today to analyze DNA. But Smith came up with a simple way to investigate the DNA in his test tubes. A solution containing large pieces of DNA is more viscous—more syrupy, in effect—than one with small pieces. So Smith measured the solution in his two test tubes with a device called a viscometer. As he had predicted, the virus DNA quickly became far less viscous. Something—some H. influenzae protein, presumably—was cutting the virus DNA into little pieces.

    “So I immediately knew this had to be a restriction enzyme,” Smith said. “It was a wonderful result—five minutes, and you know you have a discovery.”

    That instant gratification was followed by months of tedium, as Smith and his colleagues sorted through the proteins in their cell extracts until at last they identified a restriction enzyme. They also discovered a methylation enzyme that protected H. influenzae’s own DNA from destruction by shielding it with carbon and hydrogen.

    Once Smith and his colleagues published the remarkable details of their restriction enzymes, other scientists began to investigate them as well. They didn’t just study the enzymes, though—they began employing them as a tool. In 1972, Paul Berg, a biologist at Stanford University, used restriction enzymes to make cuts in the DNA of SV40 viruses, and then used other enzymes to attach the DNA from another virus to those loose ends. Berg thus created a single piece of DNA made up of genetic material from two species.

    A pack of scientists followed Berg’s lead. They realized that they could use restriction enzymes to insert genes from many different species into bacteria, which could then churn out proteins from those genes. In effect, bacteria could be transformed into biological factories.

    In 1978, Hamilton Smith got a call from Stockholm. He learned that he was sharing that year’s Nobel Prize in Medicine with Werner Arber and Daniel Nathans, another Johns Hopkins scientist who had followed up on Smith’s enzyme research with experiments of his own. Smith was as flummoxed as he was delighted.

    “They caught me off-guard,” Smith said. “I always looked up to the Nobelists as being incredibly smart people who had accomplished some world-shaking thing. It just didn’t seem like I was in that league.”

    But already the full impact of his work was starting to become clear. Companies sprouted up that were dedicated to using restriction enzymes to modify DNA. The first commercial application of this technology came from Genentech, a company founded in 1976. Genentech scientists used restriction enzymes to create a strain of E. coli that carried the gene for human insulin. Previously, people with diabetes could only purchase insulin extracted from the pancreases of cows and pigs. Genentech sold insulin produced by swarms of bacteria reared in giant metal drums.

    Over the years, scientists have built on Smith’s initial successes by finding new tools for manipulating DNA. Yet even today, researchers make regular use of restriction enzymes to slice open genes. “They’re still absolutely crucial,” said Carlson. “If you want to put a specific sequence of DNA in another sequence, it’s still most often restriction enzymes that you use to do that.”

    And as Smith has watched restriction enzymes become powerful and versatile, he has slowly overcome his case of Nobel imposter syndrome. “It probably was okay to get it,” he admitted.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Welcome to Nautilus. We are delighted you joined us. We are here to tell you about science and its endless connections to our lives. Each month we choose a single topic. And each Thursday we publish a new chapter on that topic online. Each issue combines the sciences, culture and philosophy into a single story told by the world’s leading thinkers and writers. We follow the story wherever it leads us. Read our essays, investigative reports, and blogs. Fiction, too. Take in our games, videos, and graphic stories. Stop in for a minute, or an hour. Nautilus lets science spill over its usual borders. We are science, connected.

     
  • richardmitnick 1:34 pm on February 7, 2017 Permalink | Reply
    Tags: Biology, Biomathematics, , , New study is an advance toward preventing a ‘post-antibiotic era’,   

    From UCLA: “New study is an advance toward preventing a ‘post-antibiotic era’ “ 

    UCLA bloc

    UCLA

    February 07, 2017
    Stuart Wolpert

    UCLA biologists identify drug combinations that may be highly effective at reducing growth of deadly bacteria

    1
    UCLA’s Elif Tekin, Casey Beppler, Pamela Yeh and Van Savage are gaining insights into why certain groups of three antibiotics interact well together and others don’t.

    A landmark report by the World Health Organization in 2014 observed that antibiotic resistance — long thought to be a health threat of the future — had finally become a serious threat to public health around the world. A top WHO official called for an immediate and aggressive response to prevent what he called a “post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill.”

    A team of UCLA biologists has been responding to the challenge, exploring possible ways to defeat life-threatening antibiotic-resistant bacteria. In 2016, they reported that combinations of three different antibiotics can often overcome bacteria’s resistance to antibiotics, even when none of the three antibiotics on its own — or even two of the three together — is effective.

    Their latest work, which is published online and appears in the current print edition of the Journal of the Royal Society Interface, extends their understanding of that phenomenon and identifies two combinations of drugs that are unexpectedly successful in reducing the growth of E. coli bacteria.

    A key to the study is an understanding that using two, three or more antibiotics in combination does not necessarily make the drugs more effective in combating bacteria — in fact, in many cases, their effectiveness is actually reduced when drugs are used together — so the combinations must be chosen carefully and systematically. The new paper also provides the first detailed explanation of how the scientists created a mathematical formula that can help predict which combinations of drugs will be most effective.

    The scientists tested every possible combination of a group of six antibiotics, including 20 different combinations of three antibiotics at a time.

    Among the three-drug combinations, the researchers found two that were noticeably more effective than they had expected. Those groupings used treatments from three different classes of antibiotics, so the combinations used a wide range of mechanisms to fight the bacteria. (Five of the three-drug combinations were less effective than they expected, and the other 13 groupings performed as they predicted.)

    2
    Pamela Yeh. Reed Hutchinson/UCLA

    “So many bacteria are now so resistant to antibiotics,” said Pamela Yeh, the study’s senior author and a UCLA assistant professor of ecology and evolutionary biology. “We have a logical, methodical way to identify three-drug combinations to pursue. We think it’s vital to have this framework for identifying the best possible combinations of antibiotics.”

    The researchers have identified cases where the effects of the interactions are larger than the sum of the parts.

    “Doctors may want to super-efficiently kill the bacteria, and that is what these enhanced interactions make possible,” said lead author Casey Beppler, who was an undergraduate in Yeh’s laboratory and is now a graduate student at UC San Francisco.

    For the current study, the scientists evaluated the drug combinations on plates in a lab. Beppler said a next step will be to test the most effective combinations in mice.

    In addition to reporting on how well various combinations of antibiotics worked, the paper also presents a mathematical formula the biologists developed for analyzing how three or more factors interact and of explaining complex, unexpected interactions. The framework would be useful for solving other questions in the sciences and social sciences in which researchers analyze how three or more components might interact — for example, how climate is affected by the interplay among temperature, rainfall, humidity and ocean acidity.

    The biologists are gaining a deep understanding of why certain groups of three antibiotics interact well together, and others don’t, said Van Savage, a co-author of the paper and a UCLA professor of ecology and evolutionary biology and of biomathematics.

    Beppler said more research is needed to determine which combinations are optimal for specific diseases and for specific parts of the body. And the researchers now are using the mathematical formula to test combinations of four antibiotics.

    Co-authors of the new research are Elif Tekin, a UCLA graduate student in Savage’s laboratory; Zhiyuan Mao, Cynthia White, Cassandra McDiarmid and Emily Vargas, who were undergraduates in Yeh’s laboratory; and Jeffrey H. Miller, a UCLA distinguished professor of microbiology, immunology and molecular genetics.

    Yeh’s research was funded by the Hellman Foundation. Savage’s research was funded by a James S. McDonnell Foundation Complex Systems Scholar Award and from the National Science Foundation. Beppler received funding from the National Institutes of Health Initiative to Maximize Student Development.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

     
  • richardmitnick 3:41 pm on February 4, 2017 Permalink | Reply
    Tags: , “Giant acceleration of diffusion” or GAD, Biology, , Brownian motion, , ,   

    From Brown: “Research pushes concept of entropy out of kilter” 

    Brown University
    Brown University

    [THIS POST IS DEDICATED TO EBM, READY TO ROCK THE CAMPUS]

    February 2, 2017
    Kevin Stacey
    kevin_stacey@brown.edu
    401-863-3766

    Entropy, the measure of disorder in a physical system, is something that physicists understand well when systems are at equilibrium, meaning there’s no external force throwing things out of kilter. But new research by Brown University physicists takes the idea of entropy out of its equilibrium comfort zone.

    The research, published in Physical Review Letters, describes an experiment in which the emergence of a non-equilibrium phenomenon actually requires an entropic assist.

    1
    DNA drag race. Fluorescent stained DNA molecules make their way across of fluid channel pocked with tiny pits. The pits act as “entropic barriers.”
    Stein Lab / Brown University

    “It’s not clear what entropy even means when you’re moving away from equilibrium, so to have this interplay between a non-equilibrium phenomenon and an entropic state is surprising,” said Derek Stein, a Brown University physicist and co-author of the work. “It’s the tension between these two fundamental things that is so interesting.”

    The phenomenon the research investigated is known as “giant acceleration of diffusion,” or GAD. Diffusion is the term used to describe the extent to which small, jiggling particles spread out. The jiggling refers to Brownian motion, which describes the random movement of small particles as a result of collisions with surrounding particles. In 2001, a group of researchers developed a theory of how Brownian particles would diffuse in a system that was pushed out of equilibrium.

    Imagine jiggling particles arranged on a surface with undulating bumps like a washboard. Their jiggle isn’t quite big enough to enable the particles to jump over the bumps in the board, so they don’t diffuse much at all. However, if the board were tilted to some degree (in other words, moved out of equilibrium) the bumps would become easier to jump over in the downward-facing direction. As tilt begins to increase, some particles will jiggle free of the washboard barriers and run down the board, while others will stay put. In physics terms, the particles have become more diffusive — more spread-out — as the system is moved out of equilibrium. The GAD theory quantifies this diffusivity effect and predicts that as tilt starts to increase, diffusivity accelerates. When the tilt passes the point where all the particles are able to jiggle free and move down the washboard, then diffusivity decreases again.

    The theory is important, Stein says, because it’s one of only a few attempts to make solid predictions about how systems behave away from equilibrium. It’s been tested in a few other settings and has been found to make accurate predictions.

    But Stein and his team wanted to test the theory in an unfamiliar setting — one that introduces entropy into the mix.

    For the experiment, Stein and his colleagues placed DNA strands into nanofluidic channels — essentially, tiny fluid-filled hallways through which the molecules could travel. The channels were lined however with nanopits — tiny rectangular depressions that create deep spots within the relatively narrower channels. At equilibrium, DNA molecules tend to arrange themselves in disordered, spaghetti-like balls. As a result, when a molecule finds its way into a nanopit where it has more room to form a disordered ball, it tends to stay stuck there. The pits can be seen as being somewhat like the dips between bumps on the theoretical GAD washboard, but with a critical difference: The only thing actually holding the molecule in the pit is entropy.

    “This molecule is randomly jiggling around in the pit — randomly selecting different configurations to be in — and the number of possible configurations is a measure of the molecule’s entropy,” Stein explained. “It could, at some point, land on a configuration that’s thin enough to fit into the channel outside the pit, which would allow it to move from one pit to another. But that’s unlikely because there are so many more shapes that don’t go through than shapes that do. So the pit becomes an ‘entropic barrier.’”

    Stein and his colleagues wanted to see if the non-equilibrium GAD dynamic would still emerge in a system where the barriers were entropic. They used a pump to apply pressure to the nanofluidic channels, pushing them out of equilibrium. They then measured the speeds of each molecule to see if GAD emerged. What they saw was largely in keeping with the GAD theory. As the pressure increased toward a critical point, the diffusivity of the molecules increased — meaning some molecules zipped across the channel while others stayed stuck in their pits.

    “It wasn’t at all clear how this experiment would come out,” Stein said. “This is a non-equilibrium phenomenon that requires barriers, but our barriers are entropic and we don’t understand entropy away from equilibrium.”


    Anastasios Matzavinos, a professor of applied math at Brown, developed computer simulations of the experiment to help understand the forces at play.

    The fact that the barriers remained raises interesting questions about the nature of entropy, Stein says.

    “Non-equilibrium and entropy are two concepts that are kind of at odds, but we show a situation in which one depends on the other,” he said. “So what’s the guiding principle that tells what the tradeoff is between the two? The answer is: We don’t have one, but maybe experiments like this can start to give us a window into that.”

    In addition to the more profound implications, there may also be practical applications for the findings, Stein says. The researchers showed that they could estimate the tiny piconewton forces pushing the DNA forward just by analyzing the molecules’ motion. For reference, one newton of force is roughly the weight of an average apple. A piconewton is one trillionth of that.

    The experiment also showed that, with the right amount of pressure, the diffusivity of the DNA molecules was increased by factor of 15. So a similar technique could be useful in quickly making mixtures. If such a technique were developed to take advantage of GAD, it would be a first, Stein says.

    “No one has ever harnessed a non-equilibrium phenomenon for anything like that,” he said. “So that would certainly be an interesting possibility.”

    The work was led by Stein’s graduate student Daniel Kim. Co-authors were Clark Bowman, Jackson T. Del Bonis-O’Donnell and Anastasios Matzavinos, all from Brown. The work was supported by the National Science Foundation.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition
    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

     
  • richardmitnick 3:19 pm on February 4, 2017 Permalink | Reply
    Tags: , Biology, Coxsackievirus B1, Enteroviruses, , , Wyss Institute’s human gut-on-a-chip goes viral   

    From Wyss: “Wyss Institute’s human gut-on-a-chip goes viral” 

    Harvard bloc tiny
    Wyss Institute bloc
    Wyss Institute

    February 1, 2017
    No writer credit found

    Enteroviruses enter the human body through the digestive or respiratory tract and from there spread to other sites in the body where they can cause a variety of serious health threats including meningitis, pancreatitis, myocarditis, the death of motor neurons, and perhaps even help trigger diabetes. However, they remain a challenge to study because they cannot be grown in conventional human cell cultures. Yet, understanding how enteroviruses invade gastrointestinal cells, multiply within them, and are released to other sites in the body could be key to ending the present dearth of specific anti-viral therapies and vaccines.

    1
    As shown in these immunofluorescence images, the research team recapitulated the typical epithelial microvilli architecture of the human gut in a microchannel of a microfluidic chip with cell nuclei shown in blue and the cytoskeleton that enables each cell to assume and maintain its shape in the microvilli structure shown in red (left image). Upon infection with a clinical Coxsackievirus B1 strain (green), the epithelium produced and secreted additional viral particles that induced the break-down of the tissue’s normal architecture. Credit: Wyss Institute at Harvard University.

    Towards solving this problem, a multidisciplinary team of tissue engineers and biologists at Harvard’s Wyss Institute for Biologically Inspired Engineering working alongside scientists from the Molecular Virology Team at the U.S. Food and Drug Administration (FDA)’s Center for Food Safety and Applied Nutrition now have leveraged the Wyss Institute’s previously developed human gut-on-a-chip to mimic the entry, host cell-interaction and multiplication of a pathogenic clinical strain of Coxsackievirus using gut epithelium outside the human body. Their findings are reported in PLoS One.

    “We teamed up with FDA researchers to show for the first time that an enterovirus can be successfully cultured in a microfluidic human Gut Chip system. We were excited to find that the organ-on-a-chip approach offers a potential new way to study these viral pathogens under more physiologically relevant conditions in vitro,” said the Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who led the team. Ingber also is the Judah Folkman Professor of Vascular Biology at Boston Children’s Hospital and Harvard Medical School, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

    “Now that we have a functional minimal system in place that replicates typical host-pathogen interactions, we can start to vary the type of intestinal cells, include immune cells that may contribute to the host response to infection, or create tissues using human stem cell-derived intestinal cells to tease out virus specificities and requirements for infection,” said Ingber.

    First developed in 2012, the Wyss Institute’s human gut-on-a-chip is a transparent, hollow-channeled microfluidic device the size of a computer memory stick that recapitulates the gut microenvironment. Human intestinal epithelial cells are cultured in a microchannel on a porous membrane that separates them from a parallel microchannel that mimics a neighboring capillary blood vessel. Fluid with or without viruses is flowed through both channels and exchanged through the pores of the membrane. Suction forces are also applied to parallel hollow channels, which produce cyclic deformations in the tissue that mimic intestinal peristalsis-like motions. This culture approach results in the growth of a fully differentiated gut epithelium that exhibits three-dimensional finger-like villus structures and that harbors all of the relevant cell types of the small intestine. In 2015, the team added more complexity to their biomimicking device by co-culturing a capillary endothelium on the lower surface of the membrane as well as a bacterial gut microbiome on the lumen of the epithelial channel to model aspects of human intestinal inflammation.

    “We were able to recapitulate how Coxsackievirus B1 enters the epithelium lining the intestinal villi from the gut lumen, and show that the virus replicates inside the cells and exits them again via a specific route to go on to infect cells downstream in the channel,” said Remi Villenave, Ph.D., the study’s first author who did the work when he was a postdoctoral fellow working with Ingber. “Also inflammatory cytokines that likely contribute to intestinal tissue injury in the chip were preferentially secreted into the lumen of the intestinal channel rather than into the media transporting channel, paralleling what is seen in acute infections in people.”

    Besides Villenave and Ingber, the article is also authored by FDA researchers Samantha Wales, Efstathia Papafragkou, Christopher Elkins and Michael Kulka. Additional authors are Tiama Hamkins-Indik, James Weaver, Thomas Ferrante and Anthony Bahinski, who at the time of the study were affiliated with the Wyss Institute.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
c
Compose new post
j
Next post/Next comment
k
Previous post/Previous comment
r
Reply
e
Edit
o
Show/Hide comments
t
Go to top
l
Go to login
h
Show/Hide help
shift + esc
Cancel
%d bloggers like this: