Engineers use “DNA origami” to identify vaccine design rules
DNA molecules are highly programmable.
By folding DNA into a virus-like structure, MIT researchers have designed HIV-like particles that provoke a strong immune response from human immune cells grown in a lab dish. Such particles might eventually be used as an HIV vaccine.
The DNA particles, which closely mimic the size and shape of viruses, are coated with HIV proteins, or antigens, arranged in precise patterns designed to provoke a strong immune response. The researchers are now working on adapting this approach to develop a potential vaccine for SARS-CoV-2, and they anticipate it could work for a wide variety of viral diseases.
"The rough design rules that are starting to come out of this work should be generically applicable across disease antigens and diseases," says Darrell Irvine, who is the Underwood-Prescott Professor with appointments in the departments of Biological Engineering and Materials Science and Engineering; an associate director of MIT's Koch Institute for Integrative Cancer Research; and a member of the Ragon Institute of MGH, MIT, and Harvard.
Irvine and Mark Bathe, an MIT professor of biological engineering and an associate member of the Broad Institute of MIT and Harvard, are the senior authors of the study, which appears today in Nature Nanotechnology. The paper's lead authors are former MIT postdocs Rémi Veneziano and Tyson Moyer.
Because DNA molecules are highly programmable, scientists have been working since the 1980s on methods to design DNA molecules that could be used for drug delivery and many other applications, most recently using a technique called DNA origami that was invented in 2006 by Paul Rothemund of Caltech.
In 2016, Bathe's lab developed an algorithm that can automatically design and build arbitrary three-dimensional virus-like shapes using DNA origami. This method offers precise control over the structure of synthetic DNA, allowing researchers to attach a variety of molecules, such as viral antigens, at specific locations.
"The DNA structure is like a pegboard where the antigens can be attached at any position," Bathe says. "These virus-like particles have now enabled us to reveal fundamental molecular principles of immune cell recognition for the first time."
Natural viruses are nanoparticles with antigens arrayed on the particle surface, and it is thought that the immune system (especially B cells) has evolved to efficiently recognize such particulate antigens. Vaccines are now being developed to mimic natural viral structures, and such nanoparticle vaccines are believed to be very effective at producing a B cell immune response because they are the right size to be carried to the lymphatic vessels, which send them directly to B cells waiting in the lymph nodes. The particles are also the right size to interact with B cells and can present a dense array of viral particles.
However, determining the right particle size, spacing between antigens, and number of antigens per particle to optimally stimulate B cells (which bind to target antigens through their B cell receptors) has been a challenge. Bathe and Irvine set out to use these DNA scaffolds to mimic such viral and vaccine particle structures, in hopes of discovering the best particle designs for B cell activation.
"There is a lot of interest in the use of virus-like particle structures, where you take a vaccine antigen and array it on the surface of a particle, to drive optimal B-cell responses," Irvine says. "However, the rules for how to design that display are really not well-understood."
Other researchers have tried to create subunit vaccines using other kinds of synthetic particles, such as polymers, liposomes, or self-assembling proteins, but with those materials, it is not possible to control the placement of viral proteins as precisely as with DNA origami.
For this study, the researchers designed icosahedral particles with a similar size and shape as a typical virus. They attached an engineered HIV antigen related to the gp120 protein to the scaffold at a variety of distances and densities. To their surprise, they found that the vaccines that produced the strongest response B cell responses were not necessarily those that packed the antigens as closely as possible on the scaffold surface.
"It is often assumed that the higher the antigen density, the better, with the idea that bringing B cell receptors as close together as possible is what drives signaling. However, the experimental result, which was very clear, was that actually the closest possible spacing we could make was not the best. And, and as you widen the distance between two antigens, signaling increased," Irvine says.
The findings from this study have the potential to guide HIV vaccine development, as the HIV antigen used in these studies is currently being tested in a clinical trial in humans, using a protein nanoparticle scaffold.
Based on their data, the MIT researchers worked with Jayajit Das, a professor of immunology and microbiology at Ohio State University, to develop a model to explain why greater distances between antigens produce better results. When antigens bind to receptors on the surface of B cells, the activated receptors crosslink with each other inside the cell, enhancing their response. However, the model suggests that if the antigens are too close together, this response is diminished.
In recent months, Bathe's lab has created a variant of this vaccine with the Aaron Schmidt and Daniel Lingwood labs at the Ragon Institute, in which they swapped out the HIV antigens for a protein found on the surface of the SARS-CoV-2 virus. They are now testing whether this vaccine will produce an effective response against the coronavirus SARS-CoV-2 in isolated B cells, and in mice.
"Our platform technology allows you to easily swap out different subunit antigens and peptides from different types of viruses to test whether they may potentially be functional as vaccines," Bathe says.
Because this approach allows for antigens from different viruses to be carried on the same DNA scaffold, it could be possible to design variants that target multiple types of coronaviruses, including past and potentially future variants that may emerge, the researchers say.
Bathe was recently awarded a grant from the Fast Grants Covid-19 fund to develop their SARS-CoV-2 vaccine. The HIV research presented in the Nature Nanotechnology paper was funded by the Human Frontier Science Program, the U.S. Office of Naval Research, the U.S. Army Research Office through MIT's Institute for Soldier Nanotechnologies, the Ragon Institute, and the U.S. National Institutes of Health.
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Iranian Tolkien scholar finds intriguing parallels between subcontinental geography and famous map of Middle-earth.
- J.R.R. Tolkien hinted that his stories are set in a really ancient version of Europe.
- But a fantasy realm can be inspired by a variety of places; and perhaps so is Tolkien's world.
- These intriguing similarities with Asian topography show that it may be time to 'decolonise' Middle-earth.
Mental decolonisation<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzQzMDM0OS9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY1MDU4Mjg3N30.pKS1PLxKYeJ6WDPAcleg7NCxzDn7Pddcg9rSJaul6no/img.png?width=980" id="56ee5" class="rm-shortcode" data-rm-shortcode-id="1d2ba98946accd12f7e0070c8d10154d" data-rm-shortcode-name="rebelmouse-image" alt="Menu page for Arda.ir, the website of the Persian Tolkien Society." />
Menu page for Arda.ir, the website of the Persian Tolkien Society.
Image: Arda.ir<p>Where on earth was Middle-earth? Based on a few hints by Tolkien himself, we've always sort-of assumed that his stories of "The Hobbit" and "The Lord of the Rings" were centered on Europe, but so long ago that the shape of the coasts and the land has changed. </p><p>But perhaps that's too easy and too Eurocentric an assumption; perhaps, like so many other things these days, Tolkien's fantasy realm too is in dire need of mental decolonisation.</p><p>And here's an excellent occasion: an Iranian Tolkienologist has found intriguing hints that the writer based some of Middle-earth's topography on mountains, rivers, and islands located in and near present-day Pakistan. </p><p>As mentioned in a previous article – recently reposted on the <a href="https://www.facebook.com/VeryStrangeMaps" target="_blank">Strange Maps Facebook page</a> on the occasion of the death of Ian Holm – Tolkien admitted that "The Shire is based on rural England, and not on any other country in the world," and that "the action of the story takes place in the North-West of 'Middle-earth', equivalent in latitude to the coastlands of Europe and the north shores of the Mediterranean."<br></p>
Non-European topography<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzQzMDM1MC9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY1NTQ4MzcyMX0.891LPW42L78fdrwUhXdgOab7cbhs3YOqZK4ukIQx-Rw/img.png?width=980" id="6741c" class="rm-shortcode" data-rm-shortcode-id="2b50c57cb3b8a3a1cc8a4696c89ad954" data-rm-shortcode-name="rebelmouse-image" alt="Map of Tian-shan, the Himalayas, and the Pamirs" />
If you look at it like that, yes: that does resemble Mordor...
Image: Mohammad Reza Kamali, reproduced with kind permission<p>Extrapolating from the location of the Shire in Middle-earth and from other clues dropped by Tolkien, geophysics and geology professor Peter Bird matched the geography of Middle-earth with that of Europe (more about that in the <a href="https://bigthink.com/strange-maps/121-where-on-earth-was-middle-earth?utm_medium=Social&utm_source=Facebook&fbclid=IwAR0ZFYK1EXrf4J3B3X5_U4hSAgidgBs24ZNTYV9QEFbz2qI34OA_DpZsn70#Echobox=1592583835" target="_blank">aforementioned article</a>).</p><p>However, seeing Middle-earth as a mere palimpsest for present-day Europe is to place an undue limit on the imagination of its creator. As Tolkien also said about the shape of his world: "[It] was devised 'dramatically' rather than geologically or paleontologically."</p><p>In other words, certain parts of Middle-earth may very well have been inspired by other places than European ones. It is telling that it took a non-European connoisseur of Tolkien's topography to find some examples. <br></p>
"Seen that map before"<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzQzMDM1MS9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY1MTQ3Njc3NH0.azDO1_NWm9q9FwMpmqBOV2troOX0ajAXS4lP2bLstJI/img.png?width=980" id="1b193" class="rm-shortcode" data-rm-shortcode-id="21c3d38b14503ba8edac18c0ef1cceb0" data-rm-shortcode-name="rebelmouse-image" alt="Map of Indus river" />
The Indus river is a prominent geographical feature of Pakistan. Its course is similar to that of the Anduin, the Great River of Middle-earth.
Image: Mohammad Reza Kamali, reproduced with kind permission<p>In an article published on <a href="https://arda.ir/" target="_blank">Arda.ir</a>, the web page for the Persian Tolkien Society, Mohammad Reza Kamali writes that during several years of cartographic study, "I found that maybe there are real lands [that] could have inspired Professor Tolkien, and some of them are not in Europe."</p><p>Around 2012, Kamali's eye stopped when it came across a Google Map of Central Asia that showed the mountain chain of the Himalayas, the peaks of the Pamirs bunched together in an almost circular area, and the huge, flat oval of the Takla Makan desert, bounded to the north by the Tian-Shan mountains. </p><p>"I had seen that map before," he writes. "This is of course Mordor, the land of Sauron and the dark powers of Middle-earth, where Frodo and Sam destroy the One Ring." </p><p>In <a href="http://lotrproject.com/map" target="_blank">Tolkien's world</a>, the Himalayas transform into Ephel Duath, the Mountains of Shadow; and the Tian Shan into Ered Lithui, the Ash Mountains. And the circle-shaped Pamirs "are the same shape and in exactly the same corner as the Udûn of Mordor, where Frodo and Sam originally tried getting into Mordor, via the Black Gate."<br></p>
Similar shapes<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzQzMDM1Mi9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYxMDQyODMzNX0.KHrY7rDCNNaKKJQz-xn431APM2TqxGPCaMsqNvBe1xA/img.jpg?width=980" id="7a9fa" class="rm-shortcode" data-rm-shortcode-id="e87f1af97902201abc042640255606b2" data-rm-shortcode-name="rebelmouse-image" alt="Marine Corps helicopter flying over Tarbela Dam" />
A US Marine Corps helicopter flying over the Tarbela Dam on the Indus river in Pakistan. At its center: a former river island which may have been the inspiration for Cair Andros, a ship-shaped island in Middle-earth's Anduin river.
Image: Paul Duncan (USMC), public domain<p>Mulling over these similarities, Kamali became convinced that Tolkien's map work was heavily inspired by Asia. Looking further, he found more evidence. Consider Anduin, the Great River of Middle-earth, in whose waters the One Ring was lost for more than two thousand years. </p><p>On Tolkien's map, the Anduin bends toward the sea in a shape similar to that of another great river: the Indus, which runs the length of Pakistan. Like the Anduin, it flows to the west of a major mountain chain. A prominent feature of the Anduin is the river island of Cair Andros, just north of Osgiliath. Its name means 'Ship of Long Foam', a reference to its long and narrow shape, and the sharpness of its rocks, which split the waters of the Anduin like a prow. <br></p><p>Kamali is not entirely sure, but proposes that Tolkien may have been inspired by a similar-shaped island in the Indus. Now integrated into the Tarbela Dam, which was inaugurated in 1976, it would still have been a separate island in the 1930s and '40s, when Tolkien dreamed up his map.</p>
Kutch as Tolfalas Island<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzQzMDM1NC9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTYwOTU5NjcyNn0.869W8iiowQb9_T3laFKOUe5o5UMXuMlSITb1VxRlC2g/img.png?width=980" id="9c49e" class="rm-shortcode" data-rm-shortcode-id="548bafc6042cc7515e07f77657aa161c" data-rm-shortcode-name="rebelmouse-image" alt="Map of Kutch" />
During the rainy season, the coastal region of Kutch, near the mouth of the Indus, turns into an island that resembles Tolfalas Island, near the mouth of the Anduin.
Image: Mohammad Reza Kamali, reproduced with kind permission<p>Turning our eyes to the mouth of the Anduin and Indus, we see another pair of islands, and Kamali is more certain about the real one having inspired the fictional one. The fictional one is Tolfalas Island, the largest island in Belfalas Bay. <br></p><p>At first glance, it doesn't seem to have a real-life counterpart near where the Indus joins the Arabian Sea. But take a look at the coastal part of the Indian state of Gujarat. It is known as <em>Kutch</em>, a name which apparently refers to its alternately wet and dry states. In the rainy season, the shallow wetlands flood and Kutch becomes an island – the biggest island in the Gulf of Kutch, and not too dissimilar to Tolfalas Island. </p>
General knowledge<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzQzMDM1NS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYyMDIwODkyOH0.aInJedv3tiQo1LmW-M6D5LV699oeWNltxeYcVKWwtF0/img.jpg?width=980" id="9bc6e" class="rm-shortcode" data-rm-shortcode-id="01d97d3941f9ba732b4df35c3aedd977" data-rm-shortcode-name="rebelmouse-image" alt="British Indian Empire 1909 Imperial Gazetteer of India" />
1909 map showing British India in pink (direct British control) and yellow (princely states). Circled: Kutch, clearly recognisable as an island.
Image: Edinburgh Geographical Institute; J. G. Bartholomew and Sons, public domain<p>But are these similarities really more than coincidences? Why would Tolkien, who was based in Oxford and steeped in English lore and Germanic mythology, turn to the Indian subcontinent for topographical inspiration? Perhaps because cartographic knowledge of that part of the world was far more general in Britain then than it is now. Until the late 1940s, the countries we know today as India and Pakistan were part of the British Empire. Detailed maps of the region would have been standard fare for British atlases. </p><p>Kamali is convinced that the topographical features on Tolkien's map of Middle-earth are not mere fantasy, but derive from actual places in our world, and were 'riddled' onto the map. In that case, we may look forward to more discoveries of Tolkien's real-world inspiration. <br></p>
From Frodingham to Frodo<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzQzMDM1Ni9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY2MDkwNTE2OH0.zxa0eVWzVuySpq5wQTLSYrFjdVGWyvpXecQhQc_miy8/img.jpg?width=980" id="4ad77" class="rm-shortcode" data-rm-shortcode-id="ff9aace7fc7c111df3639a276cedf63c" data-rm-shortcode-name="rebelmouse-image" alt="Photograph of J. R. R. Tolkien in army uniform" />
J.R.R. Tolkien in 1916, when he was 24. Around that time, he was stationed near the village of Frodingham, which may have given him the inspiration for the name of the main protagonist in Lord of the Rings.
Image: public domain<p>Here's one example of Tolkienography—if that's what we can call the effect of actual geography on this particular writer's imagination—which I gleaned myself, some years ago in East Yorkshire. A local historian told me that Tolkien had been stationed in the area during the First World War, and had apparently stored away some local place names for later use. The name Frodo, he said, derived from a town where he had attended a few dances – Frodingham, a village across the Humber in northern Lincolnshire, not far from Scunthorpe (<em>Scunto</em>? We dodged a bullet there). </p><p>Whether that story is entirely true or not is beside the point. As fantasy fans know, any grail quest is ultimately about the quest, not the grail. In fact, to quote Mr Kamali, the treasure is important only because it's well hidden, "by a clever professor who enjoys riddles."</p><p><em>Unless otherwise indicated, illustrations are from Mr Kamali's <a href="https://arda.ir/the-tale-of-the-annotated-map-and-tolkien-hidden-riddles/?fbclid=IwAR3RmtU0ZdyzQGlK-iCsUjho4LA2W279fwO9dt8vv90FX2IeO3zrfMuMToU" target="_blank">article</a> on <a href="https://arda.ir/" target="_blank">Arda.ir</a>, reproduced with kind permission. </em><br></p><p><strong>Strange Maps #1036</strong></p><p><em>Got a strange map? Let me know at </em><a href="mailto:firstname.lastname@example.org">email@example.com</a><em>.</em></p>
Tea and coffee have known health benefits, but now we know they can work together.
Credit: NIKOLAY OSMACHKO from Pexels
- A new study finds drinking large amounts of coffee and tea lowers the risk of death in some adults by nearly two thirds.
- This is the first study to suggest the known benefits of these drinks are additive.
- The findings are great, but only directly apply to certain people.
Maybe you should enjoy this article with a cup of coffee or tea.<p> The <a href="https://drc.bmj.com/content/8/1/e001252?T=AU" target="_blank" rel="noopener noreferrer">study</a> involved 4,923 type 2 diabetics living in Japan. The average participant was 66 years old. All of the participants were taken from the rolls of the Fukuoka Diabetes Registry, a study geared at learning about the effects of new treatments and lifestyle changes on the health of diabetics. <br> <br> The participants filled out questionnaires concerning their health, diet, habits, and other factors. Among the questions were two focused on determining how much green tea or coffee, if any, the participants consumed over the course of a week. The health of the participants was recorded for five years. During this time, 309 of the test subjects died from a variety of causes. <br> <br> Subjects who drank more than one cup of tea or coffee per day demonstrated lower odds of dying than those who had none. Those who consumed the most tea and coffee, more than four and two cups a day, respectively, enjoyed the most significant reductions in their risk of death. This level of consumption was associated with a 40 percent lower risk of <a href="https://www.sciencedaily.com/releases/2020/10/201020190129.htm" target="_blank" rel="noopener noreferrer">death</a>. </p><p>Most interestingly, the effects of drinking tea and coffee appear to combine to reduce risk even further. Those who reported drinking two or three cups of tea a day and two or more cups of coffee were 51 percent less likely to die during the study, while those who drank a whopping four or more cups of tea and two or more cups of coffee had a 63 percent lower risk of <a href="https://www.medicalnewstoday.com/articles/diabetes-coffee-and-green-tea-might-reduce-death-risk" target="_blank" rel="noopener noreferrer">death</a>. </p>
So, should I start swimming in a vat of coffee and green tea?<iframe width="730" height="430" src="https://www.youtube.com/embed/LY0E-JQxeoY" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture" allowfullscreen></iframe><p> Not quite. </p><p> The primary takeaway from this study is that Japanese adults with type 2 diabetes who drink a lot of green tea and/or coffee die less often than similar people who do not. If this effect is caused by something in the drink, lifestyle choices people who drink that much tea all make, or something else remains unknown. The finding must be considered an association at this point. <br> <br> The eye-popping reductions in mortality rates are compared to the risk of death of others in the study. The people who died reported drinking less tea and coffee than those who lived. Unless you have several demographic and conditional similarities to the subjects of this study, you probably won't suddenly be at a two-thirds lower risk of death than your peers because you drink green tea. </p><p> Like all studies that depend on self-reporting, it is also possible that people misstated how much they consumed any one item. The study also did not look into other factors like socioeconomic status or education level, also known to impact death rates and potentially linked to coffee and tea consumption. </p><p> However, it is yet another study in the pile that suggests that <a href="https://www.healthline.com/nutrition/top-13-evidence-based-health-benefits-of-coffee" target="_blank" rel="noopener noreferrer">coffee</a> and <a href="https://www.healthline.com/nutrition/top-10-evidence-based-health-benefits-of-green-tea" target="_blank" rel="noopener noreferrer">green tea</a> are good for you. That much is increasingly <a href="https://www.health.harvard.edu/press_releases/health-benefits-linked-to-drinking-tea" target="_blank" rel="noopener noreferrer">agreed</a><a href="https://www.rush.edu/health-wellness/discover-health/health-benefits-coffee" target="_blank" rel="noopener noreferrer"> upon</a>. This study also suggests the benefits are additive, which is a new development.</p><p><br> So, while it isn't time to start the IV drip of green tea, a cup or two probably won't <a href="https://www.webmd.com/diabetes/news/20201022/coffee-green-tea-might-extend-life-for-folks-with-type-2-diabetes" target="_blank" rel="noopener noreferrer">hurt</a>. </p>
But most city dwellers weren't seeing the science — they were seeing something out of Blade Runner.
On Sept. 9, many West Coast residents looked out their windows and witnessed a post-apocalyptic landscape: silhouetted cars, buildings and people bathed in an overpowering orange light that looked like a jacked-up sunset.