Carbon Chemist

Tag: Translation

  • Even Realities G1 Smart Glasses Review: Superb Display, But Slow Info

    Even Realities G1 Smart Glasses Review: Superb Display, But Slow Info

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    I’ve been wearing the Even Realities G1 glasses for four months, and while many people have commented on my new frames, only two friends asked if my glasses were “smart.” For someone who wore Google Glass in public and lived to tell the tale, this technological anonymity is high praise indeed. They look like glasses you might actually want to wear, and they don’t draw unnecessary attention to your (OK, my) face.

    But as Clark Kent accessed his superpowers after taking off his spectacles, inversely, this mild-mannered reporter benefits from real-time language translation, access to AI, turn-by-turn navigation, and a personal assistant, all by keeping his glasses on.

    Most smart glasses, like the Ray-Ban Meta, rely on Bluetooth audio, but the G1 features a small but brilliantly effective heads-up display called the Holistic Adaptive Optical System, or HAOS. Look carefully at the lenses and you’ll see a faint rectangle in each eye. This is where a micro-LED optical engine projector displays crisp, green digital text (640 x 200 pixels). Glance up (choose the angle via the app) and a seemingly two-foot-wide text homepage appears to float around five feet in front of you. Considering all this, it’s astonishingly clever given how light and, well, normal the frames feel.

    The digitally surfaced lens is actually two bonded lenses but manages to be no thicker or heavier than a standard design. Prescription lenses cost $129 extra and, aside from the occasional glimpse of the projector screen in bright sunshine, works as well as any glasses I’ve ever owned.

    Nestled on the end of each arm you’ll find two rubbery nodules. These contain the battery, buttons, and antennae that exchange real-time data with your phone over Bluetooth. They’re marginally heavier than standard glasses, but because the weight is kept away from the nose, they feel good. The frames are made from solid magnesium and have a cool matte finish, with the temples coated in silicon for added grip. Add in screwless hinges and a classic oval shape, and you’ve got a stylish proposition even before you charge them up.

    Even Realities G1 Smart Glasses Review Superb Display But Slow Info

    Photograph: Christopher Haslam

    The charging case is equally well designed and holds enough power to recharge the glasses 2.5 times. The 60-mAh battery in the glasses has enough power for 1.5 days.

    So, they’re nice glasses—but what do they actually do?

    Virtual Assistance

    The idea of the G1 is not to replace your smartphone but rather to offer a pared-back interface that gives you help and information when you need it, then vanishes when you don’t.

    After installing the app and syncing the glasses, when you glance up you will see a screen with the date, time, battery level, and upcoming diary dates (assuming you’ve given permissions). You can also receive messages and alerts from social and messaging apps. You can’t respond to any messages, though, which seems both odd and a shame given the onboard microphones and the transcription software used.

    The right side of the main display is for QuickNotes. If you pinch the small box on the right arm, a note will flash up saying “Quick Note Recording.” When you speak, your words will be saved and displayed on the screen when you next look up. If you mention a date, time, or place, the AI assistant will add it to your diary. It’s great if you are a fan of voice notes. I’m not, but as someone who meets new people all the time but remains terrible at remembering names, I loved being able to have names, and even job titles, on display, for my eyes only.

    Translation

    Open up the Translate box on the Even Realities app, choose from one of 13 languages (including Mandarin, Japanese, and Korean), decide what language you’d like things translated into (in this case English), and press Engage. If someone then speaks to you in that language, the G1 glasses will listen, translate, and write the words on your HUD.

    Annoyingly, however, it’s no Babelfish. With one-on-one conversations it worked OK, and I enjoyed understanding my wife’s rusty Spanish. Similarly, I had success rewatching Squid Game without subtitles. But without someone wearing their own pair and translating my English, it is one-way traffic.

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  • Nuclear release of eIF1 restricts start-codon selection during mitosis

    Nuclear release of eIF1 restricts start-codon selection during mitosis

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  • I Wore Meta Ray-Bans in Montreal to Test Their AI Translation Skills. It Did Not Go Well

    I Wore Meta Ray-Bans in Montreal to Test Their AI Translation Skills. It Did Not Go Well

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    Imagine you’ve just arrived in another country, you don’t speak the language, and you stumble upon a construction zone. The air is thick with dust. You’re tired. You still stink like airplane. You try to ignore the jackhammers to decipher what the signs say: Do you need to cross the street, or walk up another block, or turn around?

    I was in exactly such a situation this week, but I came prepared. I’d flown to Montreal to spend two days testing the new AI translation feature on Meta’s Ray-Ban smart sunglasses. Within 10 minutes of setting out on my first walk, I ran into a barrage of confusing orange detour signs.

    The AI translation feature is meant to give wearers a quick, hands-free way to understand text written in foreign languages, so I couldn’t have devised a better pop quiz on how it works in real time.

    As an excavator rumbled, I looked at a sign and started asking my sunglasses to tell me what it said. Before I could finish, a harried Quebecois construction worker started shouting at me and pointing northwards, and I scurried across the street.

    Right at the start of my AI adventure, I’d run into the biggest limitation of this translation software—it doesn’t, at the moment, tell you what people say. It can only parse the written word.

    I already knew that the feature was writing-only at the moment, so that was no surprise. But soon, I’d run into its other less-obvious constraints. Over the next 48 hours, I tested the AI translation on a variety of street signs, business signs, advertisements, historical plaques, religious literature, children’s books, tourism pamphlets, and menus—with wildly varied results.

    Sometimes it was competent, like when it told me that the book I picked up for my son, Trois Beaux Bébés, was about three beautiful babies. (Correct.) It told me repeatedly that ouvert meant “open,” which, to be frank, I already knew, but I wanted to give it some layups.

    Other times, my robot translator was not up to the task. It told me that the sign for the notorious adult movie theater Cinéma L’Amour translated to … “Cinéma L’Amour.” (F for effort—Google Translate at least changed it to “Cinema Love.”)

    At restaurants, I struggled to get it to read me every item on a menu. For example, instead of telling me all of the different burger options at a brew pub, it simply told me that there were “burgers and sandwiches,” and refused to get more specific despite my wheedling.

    When I went to an Italian spot the next night, it similarly gave me a broad summary of the offerings rather than breaking them down in detail—I was told there were “grilled meat skewers,” but not, for example, that there were duck confit, lamb, and beef options, or how much they cost.

    All in all, right now, the AI translation is more of a temperamental party trick than a genuinely useful travel tool for foreign climes.

    How It Works (or Doesn’t)

    To use the AI translation, a glasses-wearer needs to say the following magic words: “Hey Meta, look at …” and then ask it to translate what it’s looking at.

    Photo of the skyline of Montreal Canada

    Courtesy of Kate Knibbs

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  • Translation Tech Is Amazing, Except When It’s Not

    Translation Tech Is Amazing, Except When It’s Not

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    Today’s language translation apps are like self-driving cars: incredibly useful, promising, nearing maturity, and almost entirely powered by machines. It’s astonishing that the technology even exists.

    Even so, machine translation is still clunky at times, if not awkward.

    Consider a recent conversation I had with my neighbor, Andre, who immigrated from Russia last year. Speaking little to no English, Andre is navigating the American Dream almost entirely through Google Translate, the most popular speech-to-speech translation app, first launched 10 years ago.

    Through his phone, Andrew and I can hold surprisingly deep conversations about where he’s from, how he thinks, how we can help each other, and what he hopes for. But on more than one occasion, Google Translate failed to communicate what Andre was trying to express, which forced us both to shrug and smile through the breakdown.

    As computers get smarter, however, Google, Apple, Microsoft, and others hope to fully remove the language barrier Andre and I shared that day. But it’ll take faster neural machine learning for that to happen, which “might be a few years out,” one developer I spoke to admitted.

    Not that the wait matters. In fact, many consumers are surprised to learn just how good today’s translation apps already are. For example, this video shows three Microsoft Researchers using the company’s live translation software to hold a conversation across multiple languages. The video is seven years old. But when I showed it to some friends, they reacted as if they’d seen the future.

    “The technology surrounding translation has come a long way in a very short time,” says Erica Richter, a spokesperson for DeepL, an award-winning machine-translation service that licenses its technology to Zendesk, Coursera, Hitachi, and other businesses. “But this hasn’t happened in parallel with consumer awareness.”

    I am a case in point. Although I’ve written about technology for nearly 20 years, I had no idea how deft Google Translate, Apple Translate, Microsoft Translator, and Amazon Alexa were until I started researching this story after my fateful encounter with Andre. The technology still isn’t capable of instant translation like you expect from a live human translator. But the turn-based speech-to-speech, text-to-speech, or photo-to-text translation is incredibly powerful.

    And it’s getting better by the year. “Translate is one of the products we built that’s entirely using artificial intelligence,” a Google spokesperson says. “Since launching Google’s Neural Machine in 2016, we’ve seen the largest improvements in accuracy to translate entire sentences rather than just phrases.”

    At the same time, half of the six apps I tried for this story sometimes botch even basic greetings. For instance, when I asked Siri and Microsoft Translator to convert “Olá, tudo bem?” from Portuguese to English, both correctly replied, “Hi, how are you?” Google Translate and Amazon Alexa, on the other hand, returned a more literal and awkward, “Hi, everything is fine?” or “Hi, is everything OK?” Not a total fail. But enough nuance to cause hesitancy or confusion on the part of the listener.

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  • Mitochondrial depletion in axons linked to protein accumulation in neurodegenerative diseases

    Mitochondrial depletion in axons linked to protein accumulation in neurodegenerative diseases

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    Researchers from Tokyo Metropolitan University have identified how proteins collect abnormally in neurons, a feature of neurodegenerative diseases like Alzheimer’s. They used fruit flies to show that depletion of mitochondria in axons can directly lead to protein accumulation. At the same time, significantly high amounts of a protein called eIF2β were found. Restoring the levels to normal led to a recovery in protein recycling. Such findings promise new treatments for neurodegenerative diseases.

    Every cell in our bodies is a busy factory, where proteins are constantly being produced and disassembled. Any changes or lapses in either the production or recycling phases can lead to serious illnesses. Neurodegenerative diseases such as Alzheimer’s and Amyotrophic Lateral Sclerosis (ALS), for example, are known to be accompanied by an abnormal build-up of proteins in neurons. However, the trigger behind this accumulation remains unknown.

    A team led by Associate Professor Kanae Ando of Tokyo Metropolitan University have been trying to determine the causes of abnormal protein build-up by studying Drosophila fruit flies, a commonly studied model organism that has many key similarities with human physiology. They focused on the presence of mitochondria in axons, the long tendril-like appendages that stretch out of neurons and form the necessary connections that allow signals to be transmitted inside our brains. It is known that the levels of mitochondria in axons can drop with age, and during the progress of neurodegenerative diseases.

    Now, the team have discovered that the depletion of mitochondria in axons has a direct bearing on protein build-up. They used genetic modification to suppress the production of milton, a key protein in the transport of mitochondria along axons. It was found that this led to abnormal levels of protein building up in fruit fly neurons, a result of the breakdown of autophagy, the recycling of proteins in cells. Through proteomic analysis, they were able to identify a significant upregulation in eIF2β, a key subunit of the eIF2 protein complex responsible for the initiation of protein production (or translation). The eIF2α subunit was also found to be chemically modified. Both of these issues hamper the healthy action of eIF2.

    Importantly, by artificially suppressing levels of eIF2β, the team discovered that they could restore the autophagy that was lost and regain some of the neuron function that was impaired due to axonal mitochondria loss. This not only shows that depletion of mitochondria in axons can cause abnormal protein accumulation, but that this happens via upregulation of eIF2β.

    As populations age and the prevalence of neurodegenerative conditions continues to increase, the team’s findings present a vital step in developing therapies to combat these serious illnesses.

    This work was supported by a Sasakawa Scientific Research Grant (2021-4087), the Takeda Science Foundation, a Hoansha Foundation Grant, a research award from the Japan Foundation for Aging and Health and the Novartis Foundation (Japan) for the Promotion of Science, a Grant-in-Aid for Scientific Research on Challenging Research (Exploratory) [JSPS KAKENHI Grant Number 19K21593], NIG-JOINT (National Institute of Genetics, 71A2018, 25A2019), and the TMU Strategic Research Fund for Social Engagement.

    Source:

    Tokyo Metropolitan University

    Journal reference:

    Shinno, K., et al. (2024). Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β. eLife. doi.org/10.7554/elife.95576.1.

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  • Study sheds light on how androgens shape sex differences at the cellular and molecular levels

    Study sheds light on how androgens shape sex differences at the cellular and molecular levels

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    Sex differences are widespread across human development, physiological processes, and diseases, making it important to characterize the impact of sex differences in these areas. Understanding the regulatory mechanisms associated with these differences, including the role of androgens, is also vital for clinical translation-;especially for diseases more prevalent in one sex.

    To answer these questions, a team led by Prof. GAO Dong and Prof. CHEN Luonan from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, Prof. BAI Fan from Peking University, and Prof. YU Chen from the Shenzhen Bay Laboratory, deeply explored the role of androgens in shaping sex differences at the molecular and cellular levels. Their study was published in Nature. 

    The researchers developed a detailed single-cell transcriptomic map from 17 different tissues of the mouse (Mus musculus). Using this dataset, they analyzed sex differences in depth and investigated how androgens influence these differences through specific molecular pathways and cell types. They also explored the implications of their findings on sex-biased diseases. 

    They then pinpointed the genes (i.e., AASB-DEGs) among these various tissues and cell types whose expression is sex-biased and directly influenced by androgens. These genes, including Egfr, Fos, and Il33, were highlighted as potential targets for precision medicine by modulating the androgen pathway. 

    The researchers also detailed how androgens affect the prevalence of certain cell types across sexes in various tissues, notably within immune cell populations. A key finding was the identification of group 2 innate lymphoid cells (ILC2s), which play a role in inflammation and enhancing PD-1 blockade therapy. Interestingly, ILC2s exhibited the highest androgen receptor (Ar) expression levels among the major immune cell types. The presence of these cells was notably affected by androgen levels, suggesting a mechanism by which androgens influence immune responses and disease susceptibility. 

    By integrating their findings with data from the UK Biobank, the researchers discovered that the most common risk genes for multiple sex-biased diseases were major histocompatibility complex (MHC) genes, some of which showed sex differences or were androgen-responsive. Cross-species analyses based on this atlas also identified associations between cell types and sex-biased diseases. 

    Overall, this study sheds light on the intricate ways in which androgens contribute to sex differences at the cellular and molecular levels and provides the foundation for developing targeted therapies for sex-biased diseases by modulating the androgen pathway. 

    Source:

    Chinese Academy of Sciences Headquarters

    Journal reference:

    Li, F., et al. (2024). Sex differences orchestrated by androgens at single-cell resolution. Nature. doi.org/10.1038/s41586-024-07291-6.

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  • Study explores factors contributing to rural-urban difference in cervical cancer screening

    Study explores factors contributing to rural-urban difference in cervical cancer screening

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    Study reveals English proficiency, income, and area-level unemployment are among the influential factors and highlights need for tailored interventions to increase screening rates. 

    In the United States, community health centers (CHCs) mainly serve historically marginalized populations. New research reveals that both before and during the COVID-19 pandemic, females receiving care at rural CHCs were less likely to be up to date with cervical cancer screening than those in urban CHCs. Factors associated with these differences included the proportion of patients with limited English proficiency and low income, as well as area-level unemployment and primary care physician density. The findings are published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society. 

    In the analysis of data from CHCs in operation across all 50 states and the District of Columbia, investigators found that 38.2% of females receiving care at rural CHCs were up to date on cervical cancer screening during 2014–2019, compared with 43.0% of females receiving care at urban CHCs. This difference widened during the pandemic to 43.5% versus 49.0%. 

    The rural-urban difference in screening was mostly explained by differences in CHC-level proportions of patients with limited English proficiency. This accounted for 55.9% of the difference. Differences in the proportions of patients with income below the poverty level accounted for 12.3% of the rural-urban difference in screening, and the proportion of females aged 21–64 years accounted for 9.8% of the difference. Differences in area-level unemployment accounted for 3.4% of the difference, and differences in primary care physician density accounted for 3.2% of the difference. Differences between rural-urban CHCs were counterbalanced (meaning that differences were reduced) by the proportion of uninsured patients and patients with Medicaid coverage. (There were lower proportions of uninsured or Medicaid patients in rural CHCs. If rural CHCs had equal or larger proportions of uninsured or Medicaid patients as urban CHCs, the rural-urban gap would have been larger.) 

    The contributing factors’ effects on rural-urban differences in cervical cancer screening generally increased during the pandemic in 2020–2021. 

    “In our study, a higher proportion of patients best served in a language other than English in urban CHCs was the top contributor to rural-urban differences in up-to-date cervical cancer screening. A possible explanation for this finding might be greater access to language translation services in urban CHCs, as clinics serving a greater proportion of racial and ethnic minority groups are more likely to provide better translation services,” said lead author Hyunjung Lee, PhD, MS, MPP, MBA, of the American Cancer Society.

    Increasing access to language translation services or adaptation of patient navigator interventions might improve completion and timeliness of cancer screening in CHCs and among patients with limited English proficiency, especially in rural CHCs. Insufficient funding remains a challenge to initiate and manage these activities, particularly in rural CHCs.” 

    Hyunjung Lee, PhD, MS, MPP, MBA, Lead Author, American Cancer Society

    Dr. Lee stressed that the prevalence of cervical cancer screening in CHCs is generally lower than in the general population, underscoring the need to improve cancer screening rates in both rural and urban CHCs to detect the disease at earlier stages, when treatment is most successful.

    Source:

    Journal reference:

    Lee, H., et al. (2024). Factors contributing to differences in cervical cancer screening in rural and urban community health centers. Cancer. doi.org/10.1002/cncr.35265.

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  • UQ researchers use new dosing technology to enhance ICU antibiotic treatment

    UQ researchers use new dosing technology to enhance ICU antibiotic treatment

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    University of Queensland researchers have used dosing software to accelerate the effects of antibiotics in patients being treated for sepsis in Intensive Care Units.

    UQ researchers use new dosing technology to enhance ICU antibiotic treatment
    Dosing software improved antibiotic exposures in critically ill adults and children with sepsis. Image Credit: Adobe.

    Co-senior study author Professor Jason Roberts from UQ’s Centre for Clinical Research said the technique trialed in the DIRECT study meant patients received effective antibiotics in half the usual time, leading to faster recovery, higher quality care, cost savings and increased bed availability in the hospitals.

    “We found we could dramatically improve the accuracy and quality of the treatment provided to adults and children, meaning less time in the ICU and a faster cure,” Professor Roberts said.

    “We did this by rapidly identifying which bacteria was causing their severe infection, and then applying a personalized dosing approach to ensure each patient received the most effective dose for their needs.

    “The team used Bayesian dosing software in four adult and pediatric ICUs, leading to an estimated healthcare saving of $12,000 per patient in some groups.”

    The clinical trial was unusual because it included children and involved collaborators at four major Brisbane hospitals.

    UQCCR Principal Research Fellow and co-senior author Associate Professor Adam Irwin said improving the accuracy of infection treatment was a great outcome.

    “In this study, clinicians in pediatric and adult intensive care settings alike were confident to apply the dosing software recommendations, meaning critically ill children and adults will benefit from the results,” Dr Irwin said.

    We had ICU doctors and nurses, pharmacists, infectious diseases doctors, microbiologists and experts in health economics involved in the study.

    This research highlights our strong commitment to providing the best possible care for Queenslanders.

    We hope that further funding will allow us to demonstrate the value of this treatment approach to a broader international audience.”

    Professor Adam Irwin

    DIRECT was funded by MRFF Rapid Applied Research Translation Program Grants administered through Health Translation Queensland, and was conducted at the Herston Infectious Diseases Institute in collaboration with Metro North Health, Queensland Children’s Hospital and Metro South Health.

    The research is published in Intensive Care Medicine.

    Source:

    Journal reference:

    Chai, G.G., et al. (2024) Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis. Intensive Care Medicine. doi.org/10.1007/s00134-024-07353-3

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  • DNA origami vaccine DoriVac paves way for personalized cancer immunotherapy

    DNA origami vaccine DoriVac paves way for personalized cancer immunotherapy

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    Therapeutic cancer vaccines are a form of immunotherapy in the making that could not only destroy cancer cells in patients, but keep a cancer from coming back and spreading. Multiple therapeutic cancer vaccines are being studied in clinical trials, but despite their promise, they are not routinely used yet by clinical oncologists to treat their patients. 

    The central ingredient of therapeutic cancer vaccines is antigens, which are preferentially produced or newly produced (neoantigens) by tumor cells and enable a patient’s immune system to search and destroy the cancerous cells. In most cases, those antigens cannot act alone and need the help of adjuvant molecules that trigger a general alarm signal in immune cells known as antigen-presenting cells (APCs). APCs internalize both antigen and adjuvant molecules and present the antigens to different types of T cells. Those T cells then launch an immediate attack against the tumor, or preserve a longer-lasting memory of the tumor for future defense.

    A cancer vaccine’s effectiveness depends on the level and duration of the “alarm” its adjuvants can ring in APCs. Previously, researchers found that delivering adjuvant and antigen molecules to APCs simultaneously using nanostructures like DNA origami can increase APC activation. However, none of these approaches systematically investigated how the number and nanoscale arrangement of adjuvant molecules affect downstream tumor-directed immunity. 

    Now, a research team at the Wyss Institute at Harvard University, Dana-Farber Cancer Institute (DFCI), Harvard Medical School (HMS), and Korea Institute of Science and Technology (KIST) has created a DNA origami platform called DoriVac, whose core component is a self-assembling square block-shaped nanostructure. To one face of the square block, defined numbers of adjuvant molecules can be attached in highly tunable, nanoprecise patterns, while the opposite face can bind tumor antigens. The study found that molecules of an adjuvant known as CpG spaced exactly 3.5 nanometers apart from each other resulted in the most beneficial stimulation of APCs that induced a highly-desirable profile of T cells, including those that kill cancer cells (cytotoxic T cells), those that cause beneficial inflammation (Th-1 polarized T cells), and those that provide a long-term immune memory of the tumor (memory T cells). DoriVac vaccines enabled tumor-bearing mice to better control the growth of tumors and to survive significantly longer than control mice. Importantly, the effects of DoriVac also synergized with those of immune checkpoint inhibitors, which are a highly successful immunotherapy that is already widely used in the clinic. The findings are published in Nature Nanotechnology.

    “DoriVac’s DNA origami vaccine technology merges different nanotechnological capabilities that we have developed over the years with an ever-deepening knowledge about cancer-suppressing immune processes,” said Wyss Core Faculty member William Shih, Ph.D., who led the Wyss Institute team together with first-author Yang (Claire) Zeng, M.D., Ph.D. “We envision that in the future, antigens identified in patients with different types of tumors could be quickly loaded onto prefabricated, adjuvant-containing DNA origami to enable highly effective personalized cancer vaccines that can be paired with FDA-approved checkpoint inhibitors in combination therapies.”

    Shih is also a Professor at HMS and DFCI’s Department of Cancer Biology and, as some of the other authors, a member of the NIH-funded cross-institutional “Immuno-engineering to Improve Immunotherapy” (i3) Center based at the Wyss. 

    DNA origami rationale

    The CpG adjuvant is a synthetic strand of DNA made up of repeated CpG nucleotide motifs that mimic the genetic material from immune cell-invading bacterial and viral pathogens. Like its natural counterparts, CpG adjuvants bind to a “danger receptor” called TLR9 in immune cells, which in turn induces an inflammatory (innate) immune response that works in concert with the antigen-induced (adaptive) immune response. 

    “We knew from previous work that to trigger strong inflammatory responses, TLR9 receptors need to dimerize and aggregate into multimeric complexes binding to multiple CpG molecules. The nanoscale distances between the CpG-binding domains in effective TLR9 assemblies revealed by structural analysis fell right into the range of what we hypothesized we could mirror with DNA origami structures presenting precisely spaced CpG molecules,” explained Zeng, who was an Instructor in Medicine at the time of the study and now is a senior scientist at DFCI and Harvard Medical School (HMS). In addition to Shih, Zeng was also mentored on the project by senior authors Ju Hee Ryu, Ph.D., a Principal Researcher at KIST, and Wyss Founding Core Faculty member David Mooney, Ph.D., who also is Professor at Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), and one of the i3 Center’s Principal Investigators. 

    Zeng and the team fabricated DoriVac vaccines in which different numbers of CpG strands were spaced at 2.5, 3.5, 5, or 7 nanometers apart from each other on one face of the square block, and a model antigen was attached to the opposite face. They protected their structures from being degraded in the body using a chemical modification method that Shih’s group had developed earlier. When internalized by different types of APCs, including dendritic cells (DCs), which orchestrate tumor-directed T cell responses, the DoriVac vaccines improved the uptake of antigens compared to controls consisting of free antigen molecules. A CpG spacing of 3.5 nanometers produced the strongest and most beneficial responses in APCs, and significantly outperformed a control vaccine containing only free CpG molecules. “We were excited to find that the DoriVac vaccine preferentially induced an immune activation state that supports anti-tumor immunity, which is what researchers generally want to see in a good vaccine,” said Zeng. 

    Besides spacing, the numbers of CpG molecules in DoriVac vaccines also mattered. The team tested vaccines containing between 12 to 63 optimally spaced CpG molecules and found that 18 CpG molecules provided the best APC activation. This meant that their approach can also help limit the dosage of CpG molecules and thus minimize commonly observed toxic side effects observed with adjuvants.

    Gained in (tumor) translation

    Importantly, these in vitro trends translated to in vivo mouse tumor models. When prophylactically injected under the skin of mice, DoriVac vaccines accumulated in the closest lymph nodes where they stimulated DCs. A vaccine loaded with a melanoma antigen prevented the growth of subsequently injected aggressive melanoma cells. While all control animals had succumbed to the cancer by day 42 of the experiment, DoriVac-protected animals all were alive. DoriVac vaccines also inhibited tumor growth in mice in which the formation of melanoma tumors was already underway, with a 3.5 nanometer spacing of 18 CpG molecules again providing maximum effects on DC and T cells, and the strongest reduction in tumor growth.

    Next, the team asked whether DoriVac vaccines could also boost immune responses produced by small “neoantigens” emerging in melanoma tumors. Neoantigens are ideal targets because they are exclusively made by tumor cells. However, they often are not very immunogenic themselves, which make highly effective adjuvants an important component in neoantigen vaccines. A DoriVac vaccine customized with four neoantigens enabled the researchers to significantly suppress growth of the tumor in mice that produced the neoantigens.

    Finally, the researchers asked whether DoriVac could synergize with immune checkpoint therapy, which reactivates T cells that have been silenced in tumors. In mice, the two therapies combined resulted in the total regression of melanoma tumors, and prevented them from growing back when the animals were exposed to the same tumor cells again four months later. The animals had built up an immune memory of the tumor. The team obtained a similar vaccination efficiency in a mouse lymphoma model.

    We think that DoriVac’s value for determining a sweet spot in adjuvant delivery and enhancing the delivery and effects of coupled antigens can pave the way to more effective clinical cancer vaccines for use in patients with a variety of cancers.”


    Yang (Claire) Zeng, M.D., Ph.D., First Author

    The team is currently translating the DoriVac platform toward its clinical application, which is supported by the study’s assessment of vaccine distribution and vaccine-directed antibodies in mice, as well as cytokines produced by immune cells in response to the vaccines in vivo. 

    “The DoriVac platform is our first example of how our pursuit of what we call Molecular Robotics – synthetic bioinspired molecules that have programmable shape and function – can lead to entirely new and powerful therapeutics. This technology opens an entirely new path for development of designer vaccines with properties tailored to meet specific clinical challenges. We hope to see its rapid translation into the clinic,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Bioinspired Engineering at SEAS.

    Other authors on the study are Olivia Young, Christopher Wintersinger, Frances Anastassacos, James MacDonald, Giorgia Isinelli, Maxence Dellacherie, Miguel Sobral, Haiqing Bai, Amanda Graveline, Andyna Vernet, Melinda Sanchez, Kathleen Mulligan, Youngjin Choi, Thomas Ferrante, Derin Keskin, Geoffrey Fell, Donna Neuberg, Cathrine Wu, and Ick Chan Kwon. The study was funded by the Wyss Institute’s Validation Project and Institute Project programs, Claudia Adams Barr Program at DFCI, Korean Fund for Regenerative Medicine (award #21A0504L1), Intramural Research Program of KIST (award #2E30840), and National Institutes of Health (under the i3 Center supporting U54 grant (award #CA244726-01).

    Source:

    Wyss Institute at Harvard University

    Journal reference:

    Zeng, Y. C., et al. (2024). Fine tuning of CpG spatial distribution with DNA origami for improved cancer vaccination. Nature Nanotechnology. doi.org/10.1038/s41565-024-01615-3.

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