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  • richardmitnick 9:48 am on December 5, 2016 Permalink | Reply
    Tags: , Biology, Breakthrough Prizes, , Roeland Nusse, , , Wnt signaling proteins   

    From Stanford: “Roeland Nusse wins $3 million Breakthrough Prize” 

    Stanford University Name
    Stanford University

    12.4.16
    Krista Conger

    1
    Roeland Nusse was awarded the 2017 Breakthrough Prize in life sciences for his contributions to the understanding a signaling molecule called Wnt. Norbert von der Groeben

    The developmental biologist was honored for helping to decode how Wnt signaling proteins affect embryonic development, cancer and the activity of tissue-specific adult stem cells that repair damage after injury or disease.

    Roeland Nusse, PhD, the Virginia and Daniel K. Ludwig Professor in Cancer Research and a Howard Hughes Medical Institute investigator, was honored this evenng with a 2017 Breakthrough Prize in life sciences.

    Nusse was awarded the $3 million prize for his contributions to the understanding of how a signaling molecule called Wnt affects normal development, cancer and the functions of adult stem cells in many tissues throughout the body.

    “This is a complete surprise,” said Nusse, who is professor and chair of developmental biology. “My gratitude goes out to many people — my past and present postdoctoral scholars and graduate students and my former mentors have all contributed to the success of my research. The research and collaborative environment at Stanford and the long-term support from the Howard Hughes Medical Institute have also been fantastic. I see this award as a great honor for the entire community.”

    The Breakthrough Prizes, initiated in 2013, honor paradigm-shifting research and discovery in the fields of life sciences, fundamental physics and mathematics. In total, about $25 million was awarded at this year’s ceremony, a black-tie, red-carpet affair at the NASA Ames Research Center in Mountain View. The event was hosted by actor Morgan Freeman. The Grammy Award-winning pop star Alicia Keys provided entertainment.

    “Roel’s pioneering work has provided deep insights into an essential molecular signaling pathway that controls normal embryonic development and adult tissue repair, and that contributes to cancer when it is not properly regulated. His work has served as a model for many others in our field and accelerated further studies of these critical processes,” said Stanford President Marc Tessier-Lavigne, PhD. “We are grateful that the Breakthrough Prize recognizes the work of scientific leaders who are inspiring others to pursue discovery that is truly transformative, benefiting all of humanity.”

    Nusse’s interest in Wnt began in the 1980s as a postdoctoral scholar in the laboratory of Harold Varmus, MD, who was then on the faculty of UC-San Francisco. In 1982, Nusse discovered the Wnt1 gene, which was abnormally activated in a mouse model of breast cancer. He subsequently discovered that members of the Wnt family of proteins also play critical roles in embryonic development, cell differentiation and tissue regeneration.

    “Roel has devoted his career to identifying one of the major signaling molecules in embryonic development, and clarifying its role in cancer development and in tissue regeneration,” said Lloyd Minor, MD, dean of the School of Medicine. “The importance of Wnt signaling in these processes cannot be overestimated. His work has been the foundation of much of modern developmental biology, and we are very proud of his contributions.”

    Nusse’s more recent work has focused on understanding how Wnt family members control the function of adult stem cells in response to injury or disease. In 1996, he identified the cell-surface receptor to which Wnt proteins bind to control cells’ functions, and in 2002 he was the first to purify Wnt proteins — an essential step to understanding how they work at a molecular level.

    “My work has shifted significantly over the years due to the influence of my Stanford colleagues, although it has always been focused on Wnt,” said Nusse. “When I arrived at Stanford, I was studying the involvement of the Wnt proteins in mouse development and cancer. I then switched to fruit flies, and then to the study of adult stem cells. Stanford has supported me during this evolution of my research career.”

    Nusse’s lab is currently devoted to understanding how Wnt signaling affects the function of adult stem cells in the liver to help the organ heal after injury, as well as what role Wnt signaling might play in the development of liver cancer.

    “The Breakthrough Prizes are a sign of the times,” said Nusse. “Together with the recently announced Chan Zuckerberg Initiative, they show how the wealth of Silicon Valley is now making an impact not just in the field of computer science, but also in biomedical fields. This is very exciting.”

    Nusse is a member of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, of the Stanford Cancer Institute and of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. He was awarded the Peter Debye Prize from the University of Maastricht in 2000. He is a member of the U.S. National Academy of Sciences, the European Molecular Biology Organization and the Royal Dutch Academy of Sciences. He is also a fellow of the American Academy of Arts and Sciences.

    In all, seven $3 million Breakthrough Prizes — five in the life sciences, one in fundamental physics and one in mathematics — were awarded to 12 recipients. In addition, a special Breakthrough Prize in fundamental physics was awarded to the more than one thousand researchers who proved the existence of gravitational waves in February of 2016.

    Probing for dark matter

    2
    Peter Graham. No image credit

    In addition, three $100,000 New Horizons in Physics Prizes were awarded at the ceremony. Peter Graham, PhD, an assistant professor of physics at Stanford, shared one of them with Asimina Arvanitaki of the Perimeter Institute in Ontario, Canada, and Surjeet Rajendran of the University of California-Berkeley, for “pioneering a wide range of new experimental probes of fundamental physics.”

    Graham earned a PhD at Stanford and completed postdoctoral studies at the Stanford Institute for Theoretical Physics before joining the Stanford faculty in 2010. In 2014, he received an Early Career Award from the Department of Energy.

    Graham has developed new experiments to detect particles known as dark matter, which physicists have reason to believe exist but haven’t yet been able to detect. Physicists have theorized about what dark matter might be, and based on that work have designed experiments to detect those theorized particles. However, those experiments would miss one possible variant of what dark matter might be, known as an axion.

    “It was a scary scenario that this might be what dark matter is and our current experiments wouldn’t detect it,” Graham said.

    Graham designed new experimental approaches that would detect axions if they turn out to be what make up dark matter. “This prize is a huge honor,” Graham said. “It’s great to get recognition from the community for this new direction; it will really help this emerging field.”

    Three $100,000 New Horizons in Mathematics prizes were also awarded at the Breakthrough Prize ceremony.

    In addition, two teenagers — one from Peru and one from Singapore — each won the 2017 Breakthrough Junior Challenge. They will each receive $400,000 in educational prizes.

    The Breakthrough Prizes are funded by grants from the Brin Wojcicki Foundation, established by Google founder Sergey Brin and 23andMe founder Anne Wojcicki; Mark Zuckerberg’s fund at the Silicon Valley Community Foundation; Alibaba founder Jack Ma’s foundation; and DST Global founder Yuri Milner’s foundation. Recipients are chosen by committees comprised of prior prizewinners.

    Amy Adams, director for science communications at the Stanford News Service, contributed to this article.

    See the full article here .

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    Leland and Jane Stanford founded the University to “promote the public welfare by exercising an influence on behalf of humanity and civilization.” Stanford opened its doors in 1891, and more than a century later, it remains dedicated to finding solutions to the great challenges of the day and to preparing our students for leadership in today’s complex world. Stanford, is an American private research university located in Stanford, California on an 8,180-acre (3,310 ha) campus near Palo Alto. Since 1952, more than 54 Stanford faculty, staff, and alumni have won the Nobel Prize, including 19 current faculty members

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  • richardmitnick 11:20 am on December 4, 2016 Permalink | Reply
    Tags: , Biology, , ,   

    From Weizmann: “When Cells Are Fit” 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    07.11.2016 [I guess this has just ben in hiding.]
    No writer credit found

    How do the expression levels of numerous proteins affect a cell’s fitness?

    Tracking protein activity levels in a cell is essential to the study of such diseases as cancer which, alongside changes in the genes, involves changes in the activity levels of numerous proteins. However, deducing function, fitness and cellular well-being from the growing number of protein level measurements is still a major challenge. For example, is a two-fold – or 100-fold – range in activity for a particular protein tolerable over the population, or does it herald differences in the way that the cells carry out their tasks? Charting this connection could transform the way we diagnose, monitor and treat patients.

    1
    (l-r) Maya Lotan-Pompan, Leeat Yankielowicz Keren and Prof. Eran Segal can now look at multiple protein expression levels at once

    “Most experiments examining ranging protein activity levels have, until now, focused on single proteins. What we did was to develop a way to systematically vary activity levels for hundreds of different proteins – all in a single experiment – and accurately measure how this affects the function of the cells,” says Leeat Yankielowicz Keren, a research student in the group of Prof. Eran Segal of the Computer Science and Applied Mathematics, and Molecular Cell Biology Departments at the Weizmann Institute of Science.

    The basic idea of the experiment in Segal’s lab was to create a competition in which common bakers’ yeast cells are pitted against one another. Each cell was nearly identical to its neighbors, except for a tweak to the activity level of one of its proteins. Thousands of these genetically engineered yeast cells were grown together in lab dishes; the “winners” were those in which expression levels boosted their fitness, basically enabling the yeast to eat more, grow and divide faster.

    Segal and his group developed a high-throughput genetic engineering technique that enabled them to manipulate the activity levels of different protein levels within thousands of cells simultaneously, precisely controlling, for each, the amounts of one particular protein. With 130 different activity levels – the highest 500 times the lowest – attached to 81 different protein-encoding sequences, the researchers created something like 10,000 different variations on the basic yeast cell, assigning each a “barcode” for convenient identification. With a combination of DNA sequencing techniques and an algorithm they created to reconstruct the growth rates of the various yeast cells, the team was then able to accurately map the connections between protein levels and the fitness of the cell.

    The competition took place in two different “arenas.” In one, the yeast were fed the glucose sugar they prefer; in the second, they were fed a different kind of sugar, galactose. The team found that when the competition took place on the kind of sugar it prefers, the original, untouched version of the yeast cell was the overall winner – testimony to the efficiency of evolution. But on the second kind of sugar, others came out on top. These results showed that around 20% of the yeast’s natural protein activity levels are too low or too high for growing on this sugar. This could be relevant to biotechnology: The second sugar is cheaply and abundantly found in seaweed, and the yeast break it down into ethanol, which can be burned in place of fossil fuels. The study suggests that genetically engineering yeast to alter some of these protein levels could significantly increase the efficiency of this process.

    Mapping all the activity patterns together enabled the group to begin to see patterns in the chaos. Similar activity patterns, for example, pointed to proteins that work together. Further analysis even revealed the “math” that cells use to produce these proteins in the right ratios, for example, for the construction of complexes that require exact proportions of their various proteins.

    Some of the proteins appeared to operate in a very narrow range – levels even a bit below or above this range drastically affected the fitness of the yeast. Others seemed to be much more flexible – a little or a lot did not affect the cell’s fitness, at least for the particular growing conditions. Those showing the larger ranges in the fitness competition turned out to be proteins that ordinarily vary widely from cell to cell in the natural yeast population. These findings suggest that understanding this flexibility can shed light on how activity levels are selected in evolution.

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    Gene fitness profiles are different when yeast are grown on a sugar they normally prefer less

    For Segal and his team, the future goal is to create similar maps for protein activity levels in human cells. Such maps could form the basis of future diagnostic techniques that would be much more refined and precise than those of today, based on blood tests that already exist or can easily be developed. They might reveal the effects of diet or medications; and they could provide early diagnosis of cancer. Keren: “We want to eventually create a ‘chart’ that doctors can use to know which protein levels to check, and what levels should, ideally, be appearing in order to prevent disease.”

    Also participating in this study were Maya Lotan-Pompan and Dr. Adina Weinberger of Prof. Segal’s group, Dr. Jean Hausser and Prof. Uri Alon of the department of Molecular Cell Biology and Prof. Ron Milo of the department of Plant and Environmental Sciences.

    Science paper:
    Massively Parallel Interrogation of the Effects of Gene Expression Levels on Fitness, Cell

    See the full article here .

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

     
  • richardmitnick 9:32 am on October 9, 2016 Permalink | Reply
    Tags: Alien life could feed on cosmic rays, , Biology,   

    From Science: “Alien life could feed on cosmic rays” 

    AAAS

    AAAS

    Oct. 7, 2016
    Jessica Boddy

    1
    High-energy particles called galactic cosmic rays could be an energy source for life on other planets. Tinieder/iStockphoto

    A bizarre microbe found deep in a gold mine in South Africa could provide a model for how life might survive in seemingly uninhabitable environments through the cosmos. Known as Desulforudis audaxviator, the rod-shaped bacterium thrives 2.8 kilometers underground in a habitat devoid of the things that power the vast majority of life on Earth—light, oxygen, and carbon. Instead, this “gold mine bug” gets energy from radioactive uranium in the depths of the mine. Now, scientists predict that life elsewhere in the universe might also feed off of radiation, especially radiation raining down from space.

    “It really grabbed my attention because it’s completely powered by radioactive substances,” says Dimitra Atri, an astrobiologist and computational physicist who works for the Blue Marble Space Institute of Science in Seattle, Washington. “Who’s to say life on other worlds doesn’t do the same thing?”

    Essentially all life on Earth’s surface takes in the energy it needs through one of two processes. Plants, some bacteria, and certain other organisms collect energy from sunlight through a process called photosynthesis. In it, they use the energy from light to convert water and carbon dioxide into more complex and energetic molecules called hydrocarbons, thus storing the energy so that it can be recovered later by breaking down the molecules through a process called oxidation. Alternatively, animals and other organisms simply feed off of plants, one another, etc., to steal the energy already stored in living things.

    D. audaxviator takes a third path: It draws its energy from the radioactivity of uranium in the rock in the mine. The radiation from decaying uranium nuclei breaks apart sulfur and water molecules in the stone, producing molecular fragments such as sulfate and hydrogen peroxide that are excited with internal energy. The microbe then takes in these molecules, siphons off their energy, and spits them back out. Most of the energy produced from this process powers the bacterium’s reproduction and internal processes, but a portion of it also goes to repairing damage from the radiation.

    Atri thinks an extraterrestrial life form could easily make use of a similar system. The radiation might not come from radioactive materials on the planet itself, but rather from galactic cosmic rays (GCRs)—high-energy particles that careen through the universe after being flung out of a supernova. They’re everywhere, even on Earth, but our planet’s magnetic field and atmosphere shields us from most GCRs.

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    Desulforudis audaxviator thrive using radiation from uranium as an energy source deep in the gold mine they call home. NASA

    The surfaces of other planets like Mars are much more susceptible to cosmic rays because of their thin atmospheres and, in the case of Mars, its lack of a magnetic field. Atri argues GCRs could reach the Red Planet’s surface with enough energy left to power a tiny organism. This could also be the case on any world with a negligible atmosphere: Pluto, Earth’s moon, Jupiter’s moon Europa, Saturn’s moon Enceladus, and, theoretically, countless more outside our solar system. He does note, though, that because GCRs don’t deliver nearly as much energy as the sun, GCR-powered life would be very small, and simple, just like D. audaxviator.

    To figure out how this might work, Atri ran simulations using existing data about GCRs to see how much energy they’d provide on some of these other worlds. The numbers were clear: The small, steady shower of cosmic rays would supply enough energy to power a simple organism on all of the planets he simulated except Earth, Atri reports this week in the Journal of the Royal Society Interface. “It can’t be ruled out that life like this could exist,” he says.

    Atri thinks Mars is the best candidate to host GCR-powered life. The planet’s composition is rocky like Earth’s with plenty of minerals, and it might even have some water tucked away. Both would offer excellent mediums to be broken down by cosmic rays and gobbled up by a life form. The most essential part of the equation, though, is the thin atmosphere. “It’s funny,” Atri says, “because when we look for planets that contain life currently, we look for a very thick atmosphere. With these life forms, we’re looking for the opposite.”

    Duncan Forgan, an astrobiologist at the University of St Andrews in the United Kingdom who was not involved with the work, agrees that Mars might be harboring D. audaxviator-like life because its stable temperatures and physical makeup are similar to that of the South African gold mine. He does worry that on other planets that don’t receive light energy from a sun but still get bombarded with GCRs—such as free floating rogue planets not tied to any solar system—temperatures would dip too low and freeze life in its tracks. He also cautions that too many cosmic rays could wipe life out altogether: “Life forms like this want a steady flux of energy from cosmic rays, but not so much that it’s damaging,” he says. “They might not be able to cope with a huge bout of radiation that pops in.”

    In the future, Atri wants to bring the gold mine bug into the lab and see how it responds to cosmic radiation levels equivalent to those on Mars, Europa, and others. That data would give him more clues to whether this kind of organism could survive beyond Earth. “Desulforudis audaxviator is proof that life can thrive using almost any energy source available,” he says. “I always think of Jeff Goldblum in Jurassic Park—life finds a way.”

    See the full article here .

    The American Association for the Advancement of Science is an international non-profit organization dedicated to advancing science for the benefit of all people.

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  • richardmitnick 7:23 am on September 27, 2016 Permalink | Reply
    Tags: , Biology, Killing Superbugs with Star-Shaped Polymers instead of Antibiotics, , Shu Lam, U Melbourne   

    From University of Melbourne via Science Alert: Women in STEM – “Killing Superbugs with Star-Shaped Polymers instead of Antibiotics” Shu Lam 

    u-melbourne-bloc

    University of Melbourne

    ScienceAlert

    Science Alert

    The science world is freaking out over this 25-year-old’s answer to antibiotic resistance

    26 SEP 2016
    FIONA MACDONALD

    Could this be the end of superbugs?

    1
    Shu Lam

    A 25-year-old student has just come up with a way to fight drug-resistant superbugs without antibiotics.

    The new approach has so far only been tested in the lab and on mice, but it could offer a potential solution to antibiotic resistance, which is now getting so bad that the United Nations recently declared it a “fundamental threat” to global health.

    Antibiotic-resistant bacteria already kill around 700,000 people each year, but a recent study suggests that number could rise to around 10 million by 2050.

    In addition to common hospital superbug, methicillin-resistant Staphylococcus aureus (MRSA), scientists are now also concerned that gonorrhoea is about to become resistant to all remaining drugs.

    But Shu Lam, a 25-year-old PhD student at the University of Melbourne in Australia, has developed a star-shaped polymer that can kill six different superbug strains without antibiotics, simply by ripping apart their cell walls.

    “We’ve discovered that [the polymers] actually target the bacteria and kill it in multiple ways,” Lam told Nicola Smith from The Telegraph. “One method is by physically disrupting or breaking apart the cell wall of the bacteria. This creates a lot of stress on the bacteria and causes it to start killing itself.”

    The research has been published in Nature Microbiology, and according to Smith, it’s already being hailed by scientists in the field as “a breakthrough that could change the face of modern medicine”.

    Before we get too carried away, it’s still very early days. So far, Lam has only tested her star-shaped polymers on six strains of drug-resistant bacteria in the lab, and on one superbug in live mice.

    But in all experiments, they’ve been able to kill their targeted bacteria – and generation after generation don’t seem to develop resistance to the polymers.

    The polymers – which they call SNAPPs, or structurally nanoengineered antimicrobial peptide polymers – work by directly attacking, penetrating, and then destabilising the cell membrane of bacteria.

    Unlike antibiotics, which ‘poison’ bacteria, and can also affect healthy cells in the area, the SNAPPs that Lam has designed are so large that they don’t seem to affect healthy cells at all.

    “With this polymerised peptide we are talking the difference in scale between a mouse and an elephant,” Lam’s supervisor, Greg Qiao, told Marcus Strom from the Sydney Morning Herald. “The large peptide molecules can’t enter the [healthy] cells.”

    You can see the SNAPPs (green) surrounding and ripping apart bacterial cells below:

    2

    While the results are positive so far, it’s too early to get excited about what this could mean for humans, says Cyrille Boyer from the University of New South Wales in Australia, who wasn’t involved in the research.

    “The main advantage seems to be they can kill bacteria more effectively and selectively [than other peptides]” Boyer told Strom, before adding that the team is a long way off clinical applications.

    But what’s awesome about the new project is that, while other teams are looking for new antibiotics, Lam has found a completely different approach. And it could make all the different in the coming ‘post-antibiotic world’.

    That’s what she’s hoping, anyway.

    “For a time, I had to come in at 4am in the morning to look after my mice and my cells,” she told The Telegraph. “I wanted to be involved in some kind of research that would help solve problems … I really hope that the polymers we are trying to develop here could eventually be a solution.”

    See the full article here .

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    The University of Melbourne (informally Melbourne University) is an Australian public research university located in Melbourne, Victoria. Founded in 1853, it is Australia’s second oldest university and the oldest in Victoria. Times Higher Education ranks Melbourne as 33rd in the world, while the Academic Ranking of World Universities places Melbourne 44th in the world (both first in Australia).

    Melbourne’s main campus is located in Parkville, an inner suburb north of the Melbourne central business district, with several other campuses located across Victoria. Melbourne is a sandstone university and a member of the Group of Eight, Universitas 21 and the Association of Pacific Rim Universities. Since 1872 various residential colleges have become affiliated with the university. There are 12 colleges located on the main campus and in nearby suburbs offering academic, sporting and cultural programs alongside accommodation for Melbourne students and faculty.

    Melbourne comprises 11 separate academic units and is associated with numerous institutes and research centres, including the Walter and Eliza Hall Institute of Medical Research, Florey Institute of Neuroscience and Mental Health, the Melbourne Institute of Applied Economic and Social Research and the Grattan Institute. Amongst Melbourne’s 15 graduate schools the Melbourne Business School, the Melbourne Law School and the Melbourne Medical School are particularly well regarded.

    Four Australian prime ministers and five governors-general have graduated from Melbourne. Nine Nobel laureates have been students or faculty, the most of any Australian university

     
  • richardmitnick 7:36 am on September 24, 2016 Permalink | Reply
    Tags: , Biology, , Research at Princeton   

    From Research at Princeton: “New method identifies protein-protein interactions on basis of sequence alone (PNAS)” 

    Princeton University
    Princeton University

    September 23, 2016
    Catherine Zandonella, Office of the Dean for Research

    1
    Researchers can now identify which proteins will interact just by looking at their sequences. Pictured are surface representations of a histidine kinase dimer (HK, top) and a response regulator (RR, bottom), two proteins that interact with each other to carry out cellular signaling functions. (Image based on work by Casino, et. al. credit: Bitbol et. al 2016/PNAS.)

    Genomic sequencing has provided an enormous amount of new information, but researchers haven’t always been able to use that data to understand living systems.

    Now a group of researchers has used mathematical analysis to figure out whether two proteins interact with each other, just by looking at their sequences and without having to train their computer model using any known examples. The research, which was published online today in the journal Proceedings of the National Academy of Sciences, is a significant step forward because protein-protein interactions underlie a multitude of biological processes, from how bacteria sense their surroundings to how enzymes turn our food into cellular energy.

    “We hadn’t dreamed we’d be able to address this,” said Ned Wingreen, Princeton University‘s Howard A. Prior Professor in the Life Sciences, and a professor of molecular biology and the Lewis-Sigler Institute for Integrative Genomics, and a senior co-author of the study with Lucy Colwell of the University of Cambridge. “We can now figure out which protein families interact with which other protein families, just by looking at their sequences,” he said.

    Although researchers have been able to use genomic analysis to obtain the sequences of amino acids that make up proteins, until now there has been no way to use those sequences to accurately predict protein-protein interactions. The main roadblock was that each cell can contain many similar copies of the same protein, called paralogs, and it wasn’t possible to predict which paralog from one protein family would interact with which paralog from another protein family. Instead, scientists have had to conduct extensive laboratory experiments involving sorting through protein paralogs one by one to see which ones stick.

    In the current paper, the researchers use a mathematical procedure, or algorithm, to examine the possible interactions among paralogs and identify pairs of proteins that interact. The method was able to correctly predict 93% of the protein-protein paralog pairs that were present in a dataset of more than 20,000 known paired protein sequences, without being first provided any examples of correct pairs.

    Interactions between proteins happen when two proteins come into physical contact and stick together via weak bonds. They may do this to form part of a larger piece of machinery used in cellular metabolism. Or two proteins might interact to pass a signal from the exterior of the cell to the DNA, to enable a bacterial organism to react to its environment.

    When two proteins come together, some amino acids on one chain stick to the amino acids on the other chain. Each site on the chain contains one of 20 possible amino acids, yielding a very large number of possible amino-acid pairings. But not all such pairings are equally probable, because proteins that interact tend to evolve together over time, causing their sequences to be correlated.

    The algorithm takes advantage of this correlation. It starts with two protein families, each with multiple paralogs in any given organism. The algorithm then pairs protein paralogs randomly within each organism and asks, do particular pairs of amino acids, one on each of the proteins, occur much more or less frequently than chance? Then using this information it asks, given an amino acid in a particular location on the first protein, which amino acids are especially favored at a particular location on the second protein, a technique known as direct coupling analysis. The algorithm in turn uses this information to calculate the strengths of interactions, or “interaction energies,” for all possible protein paralog pairs, and ranks them. It eliminates the unlikely pairings and then runs again using only the top most likely protein pairs.

    The most challenging part of identifying protein-protein pairs arises from the fact that proteins fold and kink into complicated shapes that bring amino acids in proximity to others that are not close by in sequence, and that amino-acids may be correlated with each other via chains of interactions, not just when they are neighbors in 3D. The direct coupling analysis works surprisingly well at finding the true underlying couplings that occur between neighbors.

    The work on the algorithm was initiated by Wingreen and Robert Dwyer, who earned his Ph.D. in the Department of Molecular Biology at Princeton in 2014, and was continued by first author Anne-Florence Bitbol, who was a postdoctoral researcher in the Lewis-Sigler Institute for Integrative Genomics and the Department of Physics at Princeton and is now a CNRS researcher at Universite Pierre et Marie Curie – Paris 6. Bitbol was advised by Wingreen and Colwell, an expert in this kind of analysis who joined the collaboration while a member at the Institute for Advanced Study in Princeton, NJ, and is now a lecturer in chemistry at the University of Cambridge.

    The researchers thought that the algorithm would only work accurately if it first “learned” what makes a good protein-protein pair by studying ones discovered in experiments. This required that the researchers give the algorithm some known protein pairs, or “gold standards,” against which to compare new sequences. The team used two well-studied families of proteins, histidine kinases and response regulators, which interact as part of a signaling system in bacteria.

    But known examples are often scarce, and there are tens of millions of undiscovered protein-protein interactions in cells. So the team decided to see if they could reduce the amount of training they gave the algorithm. They gradually lowered the number of known histidine kinase-response regulator pairs that they fed into the algorithm, and were surprised to find that the algorithm continued to work. Finally, they ran the algorithm without giving it any such training pairs, and it still predicted new pairs with 93 percent accuracy.

    “The fact that we didn’t need a gold standard was a big surprise,” Wingreen said.

    Upon further exploration, Wingreen and colleagues figured out that their algorithm’s good performance was due to the fact that true protein-protein interactions are relatively rare. There are many pairings that simply don’t work, and the algorithm quickly learned not to include them in future attempts. In other words, there is only a small number of distinctive ways that protein-protein interactions can happen, and a vast number of ways that they cannot happen. Moreover, the few successful pairings were found to repeat with little variation across many organisms. This it turns out, makes it relatively easy for the algorithm to reliably sort interactions from non-interactions.

    Wingreen compared this observation – that correct pairs are more similar to one another than incorrect pairs are to each other – to the opening line of Leo Tolstoy’s Anna Karenina, which states, “All happy families are alike; each unhappy family is unhappy in its own way.”

    The work was done using protein sequences from bacteria, and the researchers are now extending the technique to other organisms.

    The approach has the potential to enhance the systematic study of biology, Wingreen said. “We know that living organisms are based on networks of interacting proteins,” he said. “Finally we can begin to use sequence data to explore these networks.”

    The research was supported in part by the National Institutes of Health (Grant R01-GM082938) and the National Science Foundation (Grant PHY–1305525).

    See the full article here .

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    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

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  • richardmitnick 11:19 am on September 16, 2016 Permalink | Reply
    Tags: , Biology, , , Hyperstable peptides, Institute for Protein Design,   

    From U Washington: “Super-stable peptides might be used to create ‘on-demand’ drugs” 

    U Washington

    University of Washington

    09.14.2016
    Michael McCarthy

    1
    An artist’s conception of a peptide created at the UW Medicine Institute for Protein Design. The backbone structure is shown in pink, and the molecular surface is blue. White indicates the crossbonds that stabilize the peptide’s shape. Vikram Mulligan

    2

    Scientists at the University of Washington’s Institute for Protein Design have shown it is possible to create small, hyperstable peptides that could provide the basis for developing powerful new drugs and diagnostic tests.

    “These super stable peptides provide an ideal molecular scaffold on which it should be possible to design ‘on demand’ a new generation of peptide-based drugs,” said UW Medicine protein engineering pioneer David Baker, who oversaw the research project. He is a UW professor of biochemistry.

    David Baker
    David Baker

    In a study, which appears in the journal Nature, the researchers demonstrate that not only is it possible to design peptides that fold into a wide variety of different conformations, but also that it is possible to incorporate functional groups of chemicals not normally found in peptides.

    3
    Illustrations of designed peptides with different configurations of two structures: tightly wound ribbons and flat, arrow-shaped ribbons.

    Both of these abilities could give designers even greater flexibility to create drugs that act on their molecular targets with high precision. Such drugs should not only be more potent but would also be less likely to have harmful side effects.

    Most drugs work by binding to a key section of a protein in a way that alters how the protein functions, typically by stimulating or inhibiting the protein’s activity. For the binding to occur, the drug must fit into the target site on the protein as a key fits into a lock. How close the lock-and-key fit is can often determine how well the medication works.

    Currently, most prescription drugs are either made of small molecules or much larger proteins. Both classes of drugs have advantages and disadvantages.

    Small molecule drugs, for example, tend to be easy to manufacture, tend to have a long shelf life, and are often easily absorbed. But they often don’t fit the targeted “lock” as selectively as could be hoped. This imperfect fit can result in off-target binding and side-effects that diminish their effectiveness. Protein drugs, on the other hand, often fit their target receptors very well but they are difficult to manufacture, are more unstable, and lose their potency if they are not kept refrigerated. Because of their size and instability, they need to be injected into patients.

    Peptide drugs fall in between these two classes. They are small, so they have many of advantages of small molecule drugs. But they are made of a chain of amino acids, the same components that make up proteins, so they have the potential to achieve the precision of larger protein drugs.

    The power of some tiny peptides can be observed in venomous creatures. A number of poisonous insects and sea creatures produce small peptide toxins. Those are some of the most potent pharmacologically active compounds known. Their potency is among the reasons why medical scientists are interested in tapping into beneficial uses of peptides.

    In the new study, Gaurav Bhardwaj, Vikram Khipple Mulligan, Christopher D. Bahl, senior fellows in the Baker lab, and their colleagues, developed computational methods that are now incorporated in the computer program called Rosetta.

    rosetta-screensaver
    rosettahome
    Rosetta@home, a project running on BOINC software from UC Berkeley
    BOINC WallPaper

    These methods are being used to design peptides ranging from 18 to 47 amino acids in length in 16 different conformations, called topologies.

    Originally developed by Baker and his earlier team, Rosetta uses advanced modelling algorithms to design new proteins by calculating the energies of the biochemical interactions within a protein, and between the protein and its surroundings. Because a protein will assume the shape in which the sum of these interaction energies is at its minimum, the program can calculate which shape a protein will most likely assume in nature.

    The peptides were made hyperstable by designing them to have interior crosslinking structures, called disulfide bonds, which staple together different sections of the peptide. Additional stabilization was secured by tying the two ends of the peptide chain together, a process called cyclization. The resulting constrained peptides were so stable that they were able to survive temperatures to 95 °C, nearly boiling. This survival feat would be impossible for antibody drugs.

    The researchers also showed that the design of these peptides could include amino acids not normally found in proteins. Amino acids have a property called handedness or chirality. Two amino acids can be made of the same atoms but have different arrangements, just as our hands have the same number of fingers but have two mirror-image configurations, right and left. This handedness keeps the right hand from fitting properly into a left-handed glove and vice versa.

    In nature, perhaps due to a chance event billions of years ago, amino acids in living cells are all left-handed. Right-handed amino acids are very rare in naturally occurring proteins. Nevetheless, the researchers were able to insert right-handed amino acids in their designed peptides.

    “Being able to include other types of amino acids allows us to create peptides with a much wider variety of conformations,” said Baker, “and being able to use right-handed amino acids essentially doubles your palette.”

    “By making it possible to create peptides that include ‘unnatural’ amino acids, this approach will allow researchers to explore peptide structures and function that have not been explored by nature through evolution,” Baker said.

    Today’s edition of Nature also has a special supplement, Insight The Protein World. Baker, Po-Ssu, and Scott E. Boyken authored the review article, The coming of age of de novo protein design.

    Also see coverage of the Nature hyperstable peptide design paper in Hutch News by the Fred Hutchinson Cancer Research Center.

    The National Institutes of Health provided partial support for this work through grants P50 AG005136, T32-H600035., GM094597, GM090205, and HHSN272201200025C. Additional funding was provided by The Three Dreamers.

    See the full article here .

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  • richardmitnick 2:23 pm on September 9, 2016 Permalink | Reply
    Tags: , Antibiotic resistance, , Biology, ,   

    From AAAS: “Scientists Build Giant Petri Dish to Film Bacteria Resistance” 

    AAAS

    AAAS

    8 September 2016
    Meagan Phelan

    Researchers have developed a large plate on which to film bacteria as they mutate in the presence of higher and higher concentrations of antibiotics, providing unprecedented insights into the phenomenon of antibiotic resistance.

    “Our device allows us to systematically map the different ways by which bacteria can become resistant to a range of antibiotics and antibiotic combinations,” said co-author Roy Kishony, a professor in the department of systems biology at Harvard Medical School and a principal investigator at Technion-Israel Institute of Technology.

    The ultimate goal, Kishony added, is to develop tools “that can predict the evolution of pathogens under different treatments, and better guide treatment choice.”

    “With our plate device, the evolutionary paths that the bacteria follow to achieve antibiotic resistance appear clearly and visually,” said co-author Michael Baym, a postdoctoral fellow in the Kishony Lab at Harvard Medical School, “and will hopefully let us start tailoring our approaches to treating resistance to different evolutionary modes.”

    The 2-by-4 foot petri dish used by the researchers to grow the bacteria contains nine bands at its base that can support varying concentrations of antibiotic. The results are reported in the 9 September issue of Science.

    Antibiotics have been used to treat patients since the 1940s, greatly reducing illness and death. However, these drugs have been used so frequently that the bacteria they are designed to kill have adapted to them in many cases, making the drugs less effective. At least 2 million people become infected with bacteria resistant to antibiotics each year in the United States, according to the Centers for Disease Control and Prevention, and at least 23,000 of these die as a result.

    “We know quite a bit about the internal defense mechanisms bacteria use to evade antibiotics,” Baym said, “but we don’t really know much about their physical movements across space as they adapt to survive in different environments.”

    To better understand how antibiotic resistance evolves in space and time, Baym and his colleagues developed a device called the microbial evolution growth arena plate, or MEGA-plate. The researchers used the antibiotics trimethoprim and ciprofloxacin in the MEGA plate in concentrations from zero to 10,000 times the original dose.

    On the right side of the plate where antibiotic levels were zero, Baym, Kishony, and colleagues grew Escherichia coli bacteria, which appeared white on the inky black background. Over two weeks, a camera mounted on the ceiling above the plate took periodic snapshots of the bacteria mutating.

    In the band with no antibiotic, the bacteria spread up until the point where they could no longer survive as they mingled with the first traces of antibiotic. Then, a small group of bacteria developed genetic mutations that allowed them to persist.

    1
    Researchers traced the branching patterns of bacterial evolution on the MEGA plate. | Katharine Sutliff/ Science

    As these drug-resistant mutants arose, their descendants migrated to areas of higher and higher antibiotic concentration, developing further mutations to compete with other mutants around them. As they continued their journey to the highest antibiotic concentration level, all remaining bacterial mutants had to evolve further still.

    Through this process of cumulative, successive mutations, the researchers could visualize how bacteria that are normally sensitive to antibiotics can evolve resistance to extremely high concentrations — those up to 100,000-fold higher than the one that killed their predecessors — in just over ten days.

    The bacteria were unable to adapt directly from zero antibiotic to the highest concentrations, for both drugs tested, revealing that exposure to intermediate concentrations of antibiotics is essential for the bacteria to evolve resistance.

    Initial mutations at each new band on the plate led to slower growth, hinting that bacteria adjusting to the antibiotic aren’t able to grow at ideal speed while developing mutations. Once fully resistant, however, such bacteria regained normal growth rates.

    “One of our main objectives in the lab is to reveal such evolutionary tradeoffs,” said Kishony, “whereby a bacterium becoming resistant to a drug confers a cost we might be able to exploit. We might potentially use other drugs to enhance such resistance-associated weakness.”

    Intriguingly, the researchers also found that the location of bacterial species played a role in their success in developing resistance. For example, when the researchers moved the trapped mutants — those behind their fast-moving, fit counterparts — to the “frontlines” of the growing bacteria, they were able to grow into new regions where the frontline bacteria could not.

    “What we saw suggests that evolution is not always led by the most resistant mutants,” said Baym. “The strongest mutants are, in fact, often moving behind more vulnerable strains.”

    This overturns the assumption that mutants that survive the highest concentration of a drug drive the fitness of bacterial populations; rather, it is those mutants that are both sufficiently fit and arise sufficiently close to the advancing front that lead the evolutionary road.

    The work of Baym, Kishony, and colleagues was inspired by Hollywood wizardry, the authors say. Kishony saw a digital billboard advertising the 2011 film Contagion, a grim narrative about a deadly viral pandemic. The marketing tool was built using a giant lab dish to show hordes of painted, glowing microbes creeping slowly across a dark backdrop to spell out the title of the movie.

    “This project was fun and joyful throughout,” Kishony said. “Seeing the bacteria spread for the first time was a thrill. Our MEGA-plate takes complex, often obscure, concepts in evolution, such as mutation selection, lineages, parallel evolution and clonal interference, and provides a visual seeing-is-believing demonstration of these otherwise vague ideas. It’s also a powerful illustration of how easy it is for bacteria to become resistant to antibiotics.”

    See the full article here .

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  • richardmitnick 10:59 am on September 9, 2016 Permalink | Reply
    Tags: , Biology, lncRNA, Long noncoding RNA,   

    From MIT: “Linking RNA structure and function” 

    MIT News
    MIT News
    MIT Widget

    September 8, 2016
    Anne Trafton | MIT News Office

    1
    In a new study, MIT biologists have deciphered the structure of one type of long noncoding RNA and used that information to figure out how it interacts with a cellular protein to control the development of heart muscle cells. Image: Jose-Luis Olivares/MIT

    2
    MIT biologists have deciphered the structure of a long noncoding RNA known as Braveheart. They found that the AGIL motif, at top left, is critical to the molecule’s function. Courtesy of the researchers

    Biologists have discovered how an enigmatic type of RNA helps to control cell fate.

    Several years ago, biologists discovered a new type of genetic material known as long noncoding RNA. This RNA does not code for proteins and is copied from sections of the genome once believed to be “junk DNA.”

    Since then, scientists have found evidence that long noncoding RNA, or lncRNA, plays roles in many cellular processes, including guiding cell fate during embryonic development. However, it has been unknown exactly how lncRNA exerts this influence.

    Inspired by historical work showing that structure plays a role in the function of other classes of RNA such as transfer RNA, MIT biologists have now deciphered the structure of one type of lncRNA and used that information to figure out how it interacts with a cellular protein to control the development of heart muscle cells. This is one of first studies to link the structure of lncRNAs to their function.

    “Emerging data points to fundamental roles for many of these molecules in development and disease, so we believe that determining the structure of lncRNAs is critical for understanding how they function,” says Laurie Boyer, the Irwin and Helen Sizer Career Development Associate Professor of Biology and Biological Engineering at MIT and the senior author of the study, which appears in the journal Molecular Cell on Sept. 8.

    Learning more about how lncRNAs control cell differentiation could offer a new approach to developing drugs for patients whose hearts have been damaged by cardiovascular disease, aging, or cancer.

    The paper’s lead author is MIT postdoc Zhihong Xue. Other MIT authors are undergraduate Boryana Doyle and Sarnoff Fellow Arune Gulati. Scott Hennelly, Irina Novikova, and Karissa Sanbonmatsu of Los Alamos National Laboratory are also authors of the paper.

    Probing the heart

    Boyer’s lab previously identified a mouse lncRNA known as Braveheart, which is found at higher levels in the heart compared to other tissues. In 2013, Boyer showed that this RNA molecule is necessary for normal development of heart muscle cells.

    In the new study, the researchers decided to investigate which regions of the 600-nucleotide RNA molecule are crucial to its function. “We knew Braveheart was critical for heart muscle cell development, but we didn’t know the detailed molecular mechanism of how this lncRNA functioned, so we hypothesized that determining its structure could reveal new clues,” Xue says.

    To determine Braveheart’s structure, the researchers used a technique called chemical probing, in which they treated the RNA molecule with a chemical reagent that modifies exposed RNA nucleotides. By analyzing which nucleotides bind to this reagent, the researchers can identify single-stranded regions, double-stranded helices, loops, and other structures.

    This analysis revealed that Braveheart has several distinct structural regions, or motifs. The researchers then tested which of these motifs were most important to the molecule’s function. To their surprise, they found that removing 11 nucleotides, composing a loop that represents just 2 percent of the entire molecule, halted normal heart cell development.

    The researchers then searched for proteins that the Braveheart loop might interact with to control heart cell development. In a screen of about 10,000 proteins, they discovered that a transcription factor protein called cellular nucleic acid binding protein (CNBP) binds strongly to this region. Previous studies have shown that mutations in CNBP can lead to heart defects in mice and humans.

    Further studies revealed that CNBP acts as a potential roadblock for cardiac development, and that Braveheart releases this repressor, allowing cells to become heart muscle.

    “This is one of the first studies to relate lncRNA structure to function,” says John Rinn, a professor of stem cell and regenerative biology at Harvard University, who was not involved in the research.

    “It is critical that we move toward understanding the specific functional domains and their structural elements if we are going to get lncRNAs up to speed with proteins, where we already know how certain parts play certain roles. In fact, you can predict what a protein does nowadays because of the wealth of structure-to-function relationships known for proteins,” Rinn says.

    Building a fingerprint

    Scientists have not yet identified a human counterpart to the mouse Braveheart lncRNA, in part because human and mouse lncRNA sequences are poorly conserved, even though protein-coding genes of the two species are usually very similar. However, now that the researchers know the structure of the mouse Braveheart lncRNA, they plan to analyze human lncRNA molecules to identify similar structures, which would suggest that they have similar functions.

    “We’re taking this motif and we’re using it to build a fingerprint so we can potentially find motifs that resemble that lncRNA across species,” Boyer says. “We also hope to extend this work to identify the modes of action of a catalog of motifs so that we can better predict lncRNAs with important functions.”

    The researchers also plan to apply what they have learned about lncRNA toward engineering new therapeutics. “We fully expect that unraveling lncRNA structure-to-function relationships will open up exciting new therapeutic modalities in the near future,” Boyer says.

    See the full article here .

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  • richardmitnick 8:57 am on September 9, 2016 Permalink | Reply
    Tags: , Biology, , , Genetic Engineering to Clash With Evolution,   

    From Quanta: “Genetic Engineering to Clash With Evolution” 

    Quanta Magazine
    Quanta Magazine

    September 8, 2016
    Brooke Borel

    In a crowded auditorium at New York’s Cold Spring Harbor Laboratory in August, Philipp Messer, a population geneticist at Cornell University, took the stage to discuss a powerful and controversial new application for genetic engineering: gene drives.

    Gene drives can force a trait through a population, defying the usual rules of inheritance. A specific trait ordinarily has a 50-50 chance of being passed along to the next generation. A gene drive could push that rate to nearly 100 percent. The genetic dominance would then continue in all future generations. You want all the fruit flies in your lab to have light eyes? Engineer a drive for eye color, and soon enough, the fruit flies’ offspring will have light eyes, as will their offspring, and so on for all future generations. Gene drives may work in any species that reproduces sexually, and they have the potential to revolutionize disease control, agriculture, conservation and more. Scientists might be able to stop mosquitoes from spreading malaria, for example, or eradicate an invasive species.

    The technology represents the first time in history that humans have the ability to engineer the genes of a wild population. As such, it raises intense ethical and practical concerns, not only from critics but from the very scientists who are working with it.

    Messer’s presentation highlighted a potential snag for plans to engineer wild ecosystems: Nature usually finds a way around our meddling. Pathogens evolve antibiotic resistance; insects and weeds evolve to thwart pesticides. Mosquitoes and invasive species reprogrammed with gene drives can be expected to adapt as well, especially if the gene drive is harmful to the organism — it’ll try to survive by breaking the drive.

    “In the long run, even with a gene drive, evolution wins in the end,” said Kevin Esvelt, an evolutionary engineer at the Massachusetts Institute of Technology. “On an evolutionary timescale, nothing we do matters. Except, of course, extinction. Evolution doesn’t come back from that one.”

    Gene drives are a young technology, and none have been released into the wild. A handful of laboratory studies show that gene drives work in practice — in fruit flies, mosquitoes and yeast. Most of these experiments have found that the organisms begin to develop evolutionary resistance that should hinder the gene drives. But these proof-of-concept studies follow small populations of organisms. Large populations with more genetic diversity — like the millions of swarms of insects in the wild — pose the most opportunities for resistance to emerge.

    It’s impossible — and unethical — to test a gene drive in a vast wild population to sort out the kinks. Once a gene drive has been released, there may be no way to take it back. (Some researchers have suggested the possibility of releasing a second gene drive to shut down a rogue one. But that approach is hypothetical, and even if it worked, the ecological damage done in the meantime would remain unchanged.)

    The next best option is to build models to approximate how wild populations might respond to the introduction of a gene drive. Messer and other researchers are doing just that. “For us, it was clear that there was this discrepancy — a lot of geneticists have done a great job at trying to build these systems, but they were not concerned that much with what is happening on a population level,” Messer said. Instead, he wants to learn “what will happen on the population level, if you set these things free and they can evolve for many generations — that’s where resistance comes into play.”

    At the meeting at Cold Spring Harbor Laboratory, Messer discussed a computer model his team developed, which they described in a paper posted in June on the scientific preprint site biorxiv.org. The work is one of three theoretical papers on gene drive resistance submitted to biorxiv.org in the last five months — the others are from a researcher at the University of Texas, Austin, and a joint team from Harvard University and MIT. (The authors are all working to publish their research through traditional peer-reviewed journals.) According to Messer, his model suggests “resistance will evolve almost inevitably in standard gene drive systems.”

    It’s still unclear where all this interplay between resistance and gene drives will end up. It could be that resistance will render the gene drive impotent. On the one hand, this may mean that releasing the drive was a pointless exercise; on the other hand, some researchers argue, resistance could be an important natural safety feature. Evolution is unpredictable by its very nature, but a handful of biologists are using mathematical models and careful lab experiments to try to understand how this powerful genetic tool will behave when it’s set loose in the wild.

    1
    Lucy Reading-Ikkanda for Quanta Magazine

    Resistance Isn’t Futile

    Gene drives aren’t exclusively a human technology. They occasionally appear in nature. Researchers first thought of harnessing the natural versions of gene drives decades ago, proposing to re-create them with “crude means, like radiation” or chemicals, said Anna Buchman, a postdoctoral researcher in molecular biology at the University of California, Riverside. These genetic oddities, she adds, “could be manipulated to spread genes through a population or suppress a population.”

    In 2003, Austin Burt, an evolutionary geneticist at Imperial College London, proposed a more finely tuned approach called a homing endonuclease gene drive, which would zero in on a specific section of DNA and alter it.

    Burt mentioned the potential problem of resistance — and suggested some solutions — both in his seminal paper and in subsequent work. But for years, it was difficult to engineer a drive in the lab, because the available technology was cumbersome.

    With the advent of genetic engineering, Burt’s idea became reality. In 2012, scientists unveiled CRISPR, a gene-editing tool that has been described as a molecular word processor. It has given scientists the power to alter genetic information in every organism they have tried it on. CRISPR locates a specific bit of genetic code and then breaks both strands of the DNA at that site, allowing genes to be deleted, added or replaced.

    CRISPR provides a relatively easy way to release a gene drive. First, researchers insert a CRISPR-powered gene drive into an organism. When the organism mates, its CRISPR-equipped chromosome cleaves the matching chromosome coming from the other parent. The offspring’s genetic machinery then attempts to sew up this cut. When it does, it copies over the relevant section of DNA from the first parent — the section that contains the CRISPR gene drive. In this way, the gene drive duplicates itself so that it ends up on both chromosomes, and this will occur with nearly every one of the original organism’s offspring.

    Just three years after CRISPR’s unveiling, scientists at the University of California, San Diego, used CRISPR to insert inheritable gene drives into the DNA of fruit flies, thus building the system Burt had proposed. Now scientists can order the essential biological tools on the internet and build a working gene drive in mere weeks. “Anyone with some genetics knowledge and a few hundred dollars can do it,” Messer said. “That makes it even more important that we really study this technology.”

    Although there are many different ways gene drives could work in practice, two approaches have garnered the most attention: replacement and suppression. A replacement gene drive alters a specific trait. For example, an anti-malaria gene drive might change a mosquito’s genome so that the insect no longer had the ability to pick up the malaria parasite. In this situation, the new genes would quickly spread through a wild population so that none of the mosquitoes could carry the parasite, effectively stopping the spread of the disease.

    A suppression gene drive would wipe out an entire population. For example, a gene drive that forced all offspring to be male would make reproduction impossible.

    But wild populations may resist gene drives in unpredictable ways. “We know from past experiences that mosquitoes, especially the malaria mosquitoes, have such peculiar biology and behavior,” said Flaminia Catteruccia, a molecular entomologist at the Harvard T.H. Chan School of Public Health. “Those mosquitoes are much more resilient than we make them. And engineering them will prove more difficult than we think.” In fact, such unpredictability could likely be found in any species.

    2
    A sample of malaria-infected blood contains two Plasmodium falciparum parasites. CDC/PHIL

    The three new biorxiv.org papers use different models to try to understand this unpredictability, at least at its simplest level.

    The Cornell group used a basic mathematical model to map how evolutionary resistance will emerge in a replacement gene drive. It focuses on how DNA heals itself after CRISPR breaks it (the gene drive pushes a CRISPR construct into each new organism, so it can cut, copy and paste itself again). The DNA repairs itself automatically after a break. Exactly how it does so is determined by chance. One option is called nonhomologous end joining, in which the two ends that were broken get stitched back together in a random way. The result is similar to what you would get if you took a sentence, deleted a phrase, and then replaced it with an arbitrary set of words from the dictionary — you might still have a sentence, but it probably wouldn’t make sense. The second option is homology-directed repair, which uses a genetic template to heal the broken DNA. This is like deleting a phrase from a sentence, but then copying a known phrase as a replacement — one that you know will fit the context.

    Nonhomologous end joining is a recipe for resistance. Because the CRISPR system is designed to locate a specific stretch of DNA, it won’t recognize a section that has the equivalent of a nonsensical word in the middle. The gene drive won’t get into the DNA, and it won’t get passed on to the next generation. With homology-directed repair, the template could include the gene drive, ensuring that it would carry on.

    The Cornell model tested both scenarios. “What we found was it really is dependent on two things: the nonhomologous end-joining rate and the population size,” said Robert Unckless, an evolutionary geneticist at the University of Kansas who co-authored the paper as a postdoctoral researcher at Cornell. “If you can’t get nonhomologous end joining under control, resistance is inevitable. But resistance could take a while to spread, which means you might be able to achieve whatever goal you want to achieve.” For example, if the goal is to create a bubble of disease-proof mosquitoes around a city, the gene drive might do its job before resistance sets in.

    The team from Harvard and MIT also looked at nonhomologous end joining, but they took it a step further by suggesting a way around it: by designing a gene drive that targets multiple sites in the same gene. “If any of them cut at their sites, then it’ll be fine — the gene drive will copy,” said Charleston Noble, a doctoral student at Harvard and the first author of the paper. “You have a lot of chances for it to work.”

    The gene drive could also target an essential gene, Noble said — one that the organism can’t afford to lose. The organism may want to kick out the gene drive, but not at the cost of altering a gene that’s essential to life.

    The third biorxiv.org paper, from the UT Austin team, took a different approach. It looked at how resistance could emerge at the population level through behavior, rather than within the target sequence of DNA. The target population could simply stop breeding with the engineered individuals, for example, thus stopping the gene drive.

    “The math works out that if a population is inbred, at least to some degree, the gene drive isn’t going to work out as well as in a random population,” said James Bull, the author of the paper and an evolutionary biologist at Austin. “It’s not just sequence evolution. There could be all kinds of things going on here, by which populations block [gene drives],” Bull added. “I suspect this is the tip of the iceberg.”

    Resistance is constrained only by the limits of evolutionary creativity. It could emerge from any spot along the target organism’s genome. And it extends to the surrounding environment as well. For example, if a mosquito is engineered to withstand malaria, the parasite itself may grow resistant and mutate into a newly infectious form, Noble said.

    Not a Bug, but a Feature?

    If the point of a gene drive is to push a desired trait through a population, then resistance would seem to be a bad thing. If a drive stops working before an entire population of mosquitoes is malaria-proof, for example, then the disease will still spread. But at the Cold Spring Harbor Laboratory meeting, Messer suggested the opposite: “Let’s embrace resistance. It could provide a valuable safety control mechanism.” It’s possible that the drive could move just far enough to stop a disease in a particular region, but then stop before it spread to all of the mosquitoes worldwide, carrying with it an unknowable probability of unforeseen environmental ruin.

    Not everyone is convinced that this optimistic view is warranted. “It’s a false security,” said Ethan Bier, a geneticist at the University of California, San Diego. He said that while such a strategy is important to study, he worries that researchers will be fooled into thinking that forms of resistance offer “more of a buffer and safety net than they do.”

    And while mathematical models are helpful, researchers stress that models can’t replace actual experimentation. Ecological systems are just too complicated. “We have no experience engineering systems that are going to evolve outside of our control. We have never done that before,” Esvelt said. “So that’s why a lot of these modeling studies are important — they can give us a handle on what might happen. But I’m also hesitant to rely on modeling and trying to predict in advance when systems are so complicated.”

    Messer hopes to put his theoretical work into a real-world setting, at least in the lab. He is currently directing a gene drive experiment at Cornell that tracks multiple cages of around 5,000 fruit flies each — more animals than past studies have used to research gene drive resistance. The gene drive is designed to distribute a fluorescent protein through the population. The proteins will glow red under a special light, a visual cue showing how far the drive gets before resistance weeds it out.

    Others are also working on resistance experiments: Esvelt and Catteruccia, for example, are working with George Church, a geneticist at Harvard Medical School, to develop a gene drive in mosquitoes that they say will be immune to resistance. They plan to insert multiple drives in the same gene — the strategy suggested by the Harvard/MIT paper.

    Such experiments will likely guide the next generation of computer models, to help tailor them more precisely to a large wild population.

    “I think it’s been interesting because there is this sort of going back and forth between theory and empirical work,” Unckless said. “We’re still in the early days of it, but hopefully it’ll be worthwhile for both sides, and we’ll make some informed and ethically correct decisions about what to do.”

    See the full article here .

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    Formerly known as Simons Science News, Quanta Magazine is an editorially independent online publication launched by the Simons Foundation to enhance public understanding of science. Why Quanta? Albert Einstein called photons “quanta of light.” Our goal is to “illuminate science.” At Quanta Magazine, scientific accuracy is every bit as important as telling a good story. All of our articles are meticulously researched, reported, edited, copy-edited and fact-checked.

     
  • richardmitnick 3:29 pm on September 8, 2016 Permalink | Reply
    Tags: , Biology, Drug Search for Leishmaniasis, ,   

    From Drug Search for Leishmaniasis at WCG: “Researchers Publish Findings on Potential New Treatments for Leishmaniasis” 

    New WCG Logo

    WCGLarge

    World Community Grid (WCG)

    8 Sep 2016
    By: Dr. Carlos Muskus López
    Coordinator, Molecular Biology and Computational Unit, PECET University of Antioquia

    Summary
    The Drug Search for Leishmaniasis team recently published their findings in the Journal of Computer-Aided Molecular Design. Using World Community Grid’s computing power, they have identified several drug compounds which may lead to improved treatments for this neglected and sometimes deadly disease.

    1
    One of the best ligands bound to the dihydrorootate dehydrogenase (DHODH) from Leishmania major. (a) Predicted binding within the crystal structure (b) Superimposition of the ligand conformations predicted to bind to each of the DHODH protein conformations extracted from the MD simulation

    Background

    Leishmaniasis, one of the most neglected tropical diseases in the world, infects more than two million people every year. The disease is caused by a parasite (genus Leishmania) which is transmitted between humans and animals by female sand flies. The number of cases continues to increase in tropical countries such as Bangladesh, India, Sudan, Ethiopia, Brazil, Colombia, Peru and others.

    The existing treatments for leishmaniasis can cause severe side effects. Additionally, drug-resistant parasites are causing major problems in many countries. For these reasons, there is an urgent need for new, safe and inexpensive anti-leishmaniasis drug compounds.

    Overview

    In our paper, we describe the detailed steps we took to identify protein drug targets, which included the screening of 600,000 molecules to determine which might lead to development of new treatments for the disease. Specifically, we searched for drugs which target the proteins which are essential for the survival of the parasite that causes leishmaniasis. By finding molecules that bind to these proteins, they can potentially be disabled, thus stopping the infection and curing the disease.

    The paper describes how some of the protein targets can bend and change shape, which presents some challenges in finding good candidate molecules. We discuss our approach to dealing with these problems.

    Using the results computed on World Community Grid, we selected the ten best drug candidates for test-tube experiments, which yielded very promising results. In particular, one of the compounds appears to be able to kill the leishmaniasis parasite without affecting human cells in vitro. Three additional compounds also showed promising results.

    We now plan to work to modify the three promising identified drug compounds to improve their potency, solubility and to minimize toxicity. We will also evaluate other top candidates depending on the funds we can raise. Furthermore, we are developing an open data platform with World Community Grid´s results so that other researchers can mine our data to detect additional drug hits or leads.

    We are grateful to all the World Community Grid volunteers who made this research possible by donating their computing power to this project.

    See the full article here.

    Please help promote STEM in your local schools.
    STEM Icon

    Stem Education Coalition

    World Community Grid (WCG) brings people together from across the globe to create the largest non-profit computing grid benefiting humanity. It does this by pooling surplus computer processing power. We believe that innovation combined with visionary scientific research and large-scale volunteerism can help make the planet smarter. Our success depends on like-minded individuals – like you.”

    WCG projects run on BOINC software from UC Berkeley.
    BOINCLarge

    BOINC is a leader in the field(s) of Distributed Computing, Grid Computing and Citizen Cyberscience.BOINC is more properly the Berkeley Open Infrastructure for Network Computing.

    BOINC WallPaper

    CAN ONE PERSON MAKE A DIFFERENCE? YOU BET!!

    MyBOINC

    “Download and install secure, free software that captures your computer’s spare power when it is on, but idle. You will then be a World Community Grid volunteer. It’s that simple!” You can download the software at either WCG or BOINC.

    Please visit the project pages-

    FightAIDS@home Phase II

    FAAH Phase II
    OpenZika

    Rutgers Open Zika

    Help Stop TB
    WCG Help Stop TB
    Outsmart Ebola together

    Outsmart Ebola Together

    Mapping Cancer Markers
    mappingcancermarkers2

    Uncovering Genome Mysteries
    Uncovering Genome Mysteries

    Say No to Schistosoma

    GO Fight Against Malaria

    Drug Search for Leishmaniasis

    Computing for Clean Water

    The Clean Energy Project

    Discovering Dengue Drugs – Together

    Help Cure Muscular Dystrophy

    Help Fight Childhood Cancer

    Help Conquer Cancer

    Human Proteome Folding

    FightAIDS@Home

    World Community Grid is a social initiative of IBM Corporation
    IBM Corporation
    ibm

    IBM – Smarter Planet
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