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Analysis: With experts concerned over rising UK case rates, where are we also with deaths, hospital admissions, long Covid and the economy?
Remember flu?Despite lockdowns holding it at bay, a small group of scientists is searching the globe for deadly new strains – and to work out what to put in next winter’s vaccines...
Researchers at MIT have developed a synthetic gene circuit that triggers the body’s immune system to attack cancers when it detects signs of the disease. The circuit, which will only activate a therapeutic response when it detects two specific cancer markers, is described in a paper published today in the journal Cell. Immunotherapy is widely seen as having considerable potential in the fight against a range of cancers. The approach has been demonstrated successfully in several recent clinical trials, according to Timothy Lu, associate professor of biological engineering and of electrical engineering and computer science at MIT. “There has been a lot of clinical data recently suggesting that if you can stimulate the immune system in the right way you can get it to recognize cancer,” says Lu, who is head of the Synthetic Biology Group in MIT’s Research Laboratory of Electronics. “Some of the best examples of this are what are called checkpoint inhibitors, where essentially cancers put up stop signs [that prevent] T-cells from killing them. There are antibodies that have been developed now that basically block those inhibitory signals and allow the immune system to act against the cancers.” However, despite this success, the use of immunotherapy remains limited by the scarcity of tumor-specific antigens — substances that can trigger an immune system response to a particular type of cancer. The toxicity of some therapies, when delivered as a systemic treatment to the whole body, for example, is another obstacle. What’s more, the treatments are not successful in all cases. Indeed, even in some of the most successful tests, only 30-40 percent of patients will respond to a given therapy, Lu says. As a result, there is now a push to develop combination therapies, in which different but complementary treatments are used to boost the immune response. So, for example, if one type of immunotherapy is used to knock out an inhibitory signal produced by a cancer, and the tumor responds by upregulating a second signal, an additional therapy could then be used to target this one as well, Lu says. “Our belief is that there is a need to develop much more specific, targeted immunotherapies that work locally at the tumor site, rather than trying to treat the entire body systemically,” he says. “Secondly, we want to produce multiple immunotherapies from a single package, and therefore be able to stimulate the immune system in multiple different ways.” To do this, Lu and a team including MIT postdocs Lior Nissim and Ming-Ru Wu, have built a gene circuit encoded in DNA designed to distinguish cancer cells from noncancer cells. The circuit, which can be customized to respond to different types of tumor, is based on the simple AND gates used in electronics. Such AND gates will only switch on a circuit when two inputs are present. Cancer cells differ from normal cells in the profile of their gene expression. So the researchers developed synthetic promoters — DNA sequences designed to initiate gene expression but only in cancer cells. The circuit is delivered to cells in the affected area of the body using a virus. The synthetic promotors are then designed to bind to certain proteins that are active in tumor cells, causing the promoters to turn on. “Only when two of these cancer promoters are activated, does the circuit itself switch on,” Lu says. This allows the circuit to target tumors more accurately than existing therapies, as it requires two cancer-specific signals to be present before it will respond. Once activated, the circuit expresses proteins designed to direct the immune system to target the tumor cells, including surface T cell engagers, which direct T cells to kill the cells. The circuit also expresses a checkpoint inhibitor designed to lift the brakes on T cell activity. When the researchers tested the circuit in vitro, they found that it was able to detect ovarian cancer cells from amongst other noncancerous ovarian cells and other cell types. They then tested the circuit in mice implanted with ovarian cancer cells, and demonstrated that it could trigger T cells to seek out and kill the cancer cells without harming other cells around them. Finally, the researchers showed that the circuit could be readily converted to target other cancer cells. “We identified other promoters that were selective for breast cancer, and when these were encoded into the circuit, it would target breast cancer cells over other types of cell,” Lu says. Ultimately, they hope they will also be able to use the system to target other diseases, such as rheumatoid arthritis, inflammatory bowel disease, and other autoimmune diseases. This advance will open up a new front against cancer, says Martin Fussenegger, a professor of biotechnology and bioengineering at ETH Zurich in Switzerland, who was not involved in the research. “First author Lior Nissim, who pioneered the very first genetic circuit targeting tumor cells, has now teamed up with Timothy Lu to design RNA-based immunomodulatory gene circuits that take cancer immunotherapy to a new level,” Fussenegger says. “The design of this highly complex tumor-killing gene circuit was made possible by meticulous optimization and integration of several components that target and program tumor cells to become a specific prey for the immune system — this is very smart technology.” The researchers now plan to test the circuit more fully in a range of cancer models. They are also aiming to develop a delivery system for the circuit, which would be both flexible and simple to manufacture and use.
Via Gerd Moe-Behrens
It will enter clinical trials to prevent and treat the infection next year.
Gene transfer is seen as a hopeful therapy for Alzheimer's and Parkinson's patients. The approach involves using harmless laboratory-produced viruses to introduce important genes into the brain cells. In a study on mice
Via Gilbert C FAURE
The 1918 influenza pandemic probably infected one-third of the world's population at the time — 500 million people. It killed between 50 million and 100 million; by contrast, Second World War deaths numbered around 60 million. Why is this catastrophe
Via Ed Rybicki
From Canada, the ovillanta is a clever — and highly effective — mosquito trap made from the pests' favourite breeding spot.
Researchers developed a mathematical model to forecast metastatic breast cancer survival using techniques usually reserved for weather prediction and financial forecasting. They looked at 25 years of data regarding 446 patients at Memorial Sloan Kettering and focused on a subgroup who were diagnosed with localized disease but later relapsed with metastatic disease. The model shows cancer metastasis is neither random nor unpredictable.
New data on survivors shows a range of health problems, from loss of vision to arthritis. It's making researchers realize they need to learn more about how the virus affects the human body.
This 2009 publication from the FAO’s Forestry and Forest Products Division highlights why emerging infectious diseases are considered to be among today’s major challenges to science, global health and human development. Rapid changes associated with globalization, especially the rapidly increasing ease of transport, are mixing people, domestic animals, wildlife and plants, along with their parasites and pathogens, at a frequency and in combinations that are unprecedented.
Following the WHO decision that it was ethical to use untested drugs on Ebola patients if it gave them a possibility of recovery, Canada says it will donate up to 1,000 doses of an experimental Ebola vaccine to help battle the disease's outbreak in West Africa.
Life is a programming language, and molecular biologist Andrew Hessel thinks that it will be increasingly available to anyone interested in designing with the building blocks of life.
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Zolgensma is a revolutionary gene therapy that can stop a deadly childhood condition called SMA in its tracks.It’s also one of the most expensive drugs in the world...
The pandemic has taught us that viruses are not easy to identify – and can spread like wildfire...
Recent years have witnessed an explosion of extensive geolocated datasets related to human movement, enabling scientists to quantitatively study individual and collective mobility patterns, and to generate models that can capture and reproduce the spatiotemporal structures and regularities in human trajectories. The study of human mobility is especially important for applications such as estimating migratory flows, traffic forecasting, urban planning, and epidemic modeling. In this survey, we review the approaches developed to reproduce various mobility patterns, with the main focus on recent developments. This review can be used both as an introduction to the fundamental modeling principles of human mobility, and as a collection of technical methods applicable to specific mobility-related problems. The review organizes the subject by differentiating between individual and population mobility and also between short-range and long-range mobility. Throughout the text the description of the theory is intertwined with real-world applications. Human Mobility: Models and Applications Hugo Barbosa-Filho, Marc Barthelemy, Gourab Ghoshal, Charlotte R. James, Maxime Lenormand, Thomas Louail, Ronaldo Menezes, José J. Ramasco, Filippo Simini, Marcello Tomasini
Via Complexity Digest
Most drugs work by tinkering with the behavior of proteins. Like meddlesome coworkers, these molecules are designed to latch onto their target proteins and keep them from doing what they need to do.
Via Integrated DNA Technologies
First potential new novel treatment for HIV in 10 years leverages the geometry of the HIV Capsid
New study suggests HPV-related genital infection can cause cervical, anal, vulvar, and vaginal cancers.
We present a model of contagion that unifies and generalizes existing models of the spread of social influences and micro-organismal infections. Our model incorporates individual memory of exposure to a contagious entity (e.g., a rumor or disease), variable magnitudes of exposure (dose sizes), and heterogeneity in the susceptibility of individuals. Through analysis and simulation, we examine in detail the case where individuals may recover from an infection and then immediately become susceptible again (analogous to the so-called SIS model). We identify three basic classes of contagion models which we call \textit{epidemic threshold}, \textit{vanishing critical mass}, and \textit{critical mass} classes, where each class of models corresponds to different strategies for prevention or facilitation. We find that the conditions for a particular contagion model to belong to one of the these three classes depend only on memory length and the probabilities of being infected by one and two exposures respectively. These parameters are in principle measurable for real contagious influences or entities, thus yielding empirical implications for our model. We also study the case where individuals attain permanent immunity once recovered, finding that epidemics inevitably die out but may be surprisingly persistent when individuals possess memory. A generalized model of social and biological contagion Peter Sheridan Dodds, Duncan J. Watts
Via Complexity Digest
This 63X photograph shows a mouse colon colonized with human microbiota. It won second place in the 2015 Nikon Small World Photomicrophotography Competition, which recognizes excellence in photography with the optical microscope and was taken using confocal microscopy.
The students in Anthony James’s basement insectary at the University of California, Irvine, knew they’d broken the laws of evolution when they looked at the mosquitoes’ eyes. By rights, the bugs, born from fathers with fluorescent red eyes and mothers with normal ones, should have come out only about half red. Instead, as they counted them, first a few and then by the hundreds, they found 99 percent had glowing eyes. More important than the eye color is that James’s mosquitoes also carry genes that stop the malaria parasite from growing. If these insects were ever released in the wild, their “selfish” genetic cargo would spread inexorably through mosquito populations, and potentially stop the transmission of malaria. The technology, called a “gene drive,” was built using the gene-editing technology known as CRISPR and is being reported by James, a specialist in mosquito biology, and a half dozen colleagues today in the Proceedings of the National Academy of Sciences. A functioning gene drive in mosquitoes has been anticipated for more than a decade by public health organizations as a revolutionary novel way to fight malaria. Now that it’s a reality, however, the work raises questions over whether the technology is safe enough to ever be released into the wild. “This is a major advance because it shows that gene drives will likely be effective in mosquitoes,” says Kevin Esvelt, a gene drive researcher at Harvard University’s Wyss Institute. “Technology is no longer the limitation.” Starting last summer, Esvelt and other scientists began warning that gene drives were about to jump from theory to reality (see “Protect Society from Our Inventions, Says Genome Editing Scientists”) and needed more attention by regulators and the public. The National Academy of Sciences is studying the science and ethics of the technology and plans to release recommendations next year on “responsible conduct” by scientists and companies. Gene drives are just the latest example of the fantastic power of CRISPR editing to alter the DNA of living things, which has already set off a debate over the possibility that gene editing could be used to generate designer human babies (see “Engineering the Perfect Baby”). But Henry Greely, a law professor and bioethics specialist at Stanford, says environmental uses are more worrisome than a few modified people. “The possibility of remaking the biosphere is enormously significant, and a lot closer to realization,” he says. Malaria is caused when a mosquito bite transmits plasmodium, a single-celled parasite. It’s treatable, yet every year, 670,000 people die from malaria, the majority of them young children in sub-Saharan Africa. James says his mosquitoes are the culmination of decades of mostly obscure, unheralded work by a few insect specialists toward constructing a genetic solution to malaria. It finally became possible this year when scientists in the laboratory of Ethan Bier, a fly biologist at the University of California, San Diego, who is a coauthor of the paper, finally used CRISPR to perfect a molecular “motor” that could allow the anti-malaria genes to spread. The mosquitoes have two important genetic additions. One is genes that manufacture antibodies whenever a female mosquito has a “blood meal.” Those antibodies bind to the parasite’s surface and halt its development. Yet normally, such an engineered mosquito would pass the genes only to exactly half its offspring, since there’s a 50 percent chance any chunk of DNA would come from its mate. And since the new genes probably don’t help a mosquito much, they’d quickly peter out in the wild. That’s where CRISPR comes in. In a gene drive, components of the CRISPR system are added such that any normal gene gets edited and the genetic cargo is added to it as well. In James’s lab, practically all the mosquitoes ended up with the genetic addition, a result Esvelt calls “astounding.” What worries Esvelt is that, in his opinion, the California researchers haven’t used strict enough safety measures. He says locked doors and closed cages aren’t enough. He wants them to install a genetic “reversal drive” so the change can be undone, if necessary. “An accidental release would be a disaster with potentially devastating consequences for public trust in science and especially gene-drive interventions,” he says. “No gene-drive intervention must ever be released without popular support.” James says the experiment was safe since the mosquitoes are kept behind a series of locked, card-entry doors and because they aren’t native to California. If any escaped, they wouldn’t be able to reproduce. In fact, the whole point of a gene drive is to release it into the wild, a concept that has long been accepted, at least in theory, by public health organizations including the Gates Foundation. Now that they’re actually possible, however, alarming news headlines have compared the technology to “the next weapon of mass destruction” and even raised the specter of insect terrorism, such as mosquitoes that kill people with a toxin. Gene-drive terrorism is probably nonsense, at least for now. That’s because even if insect weapons were possible, in practice it’s unlikely a terrorist organization would invest millions in an advanced genetic-engineering program. “I have been thinking quite a bit about bad things you could do with it, and we haven’t come up with anything that would succeed,” says Bier. “There are so many bad things you could do that are easier.” Instead, Bier and James say they are convinced that engineered mosquitoes should be released as soon as possible, something they hope to do if they can find a community affected by malaria that will agree to it. “Imagine we could design a mosquito that would magically cure cancer,” says Bier. “Well, the fear of getting malaria is the same fear we have of getting cancer. In my opinion the benefits outweigh the risks, and we should move forward as aggressively as we can.”
Via Gerd Moe-Behrens
The annual estimates reflect amounts that change as a result of science, actual research projects funded, and the NIH budget. The research categories are not mutually exclusive. Individual research projects can be included in multiple categories so amounts depicted within each column of this table do not add up to 100 percent of NIH-funded research. The table shows historical data for FY 2010 through FY 2013. The FY 2014-2015 estimates are based on RCDC actual data.
To determine geographic range for Ebola virus, we tested 276 bats in Bangladesh. Five (3.5%) bats were positive for antibodies against Ebola Zaire and Reston viruses; no virus was detected by PCR. These bats might be a reservoir for Ebola or Ebola-like viruses, and extend the range of filoviruses to mainland Asia.
The World Health Organization announced on Monday that a polio sample was collected in March at Viracopos International Airport in Campinas, which is about 60 miles outside Sao Paulo, and is where many of the World Cup teams have been landing. The agency said no cases of polio have been identified and there is no evidence the disease has been transmitted.
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Elena Renken's has written an excellent article for Quanta Magazine on cell self generated gradients that guide cell migration. There are several implications for modeling and simulating cellular mechanisms and especially cancer cell migration. Very much worthwhile reading and following up on the related research.