Shadow & Light is a list of curated photography stories, features, techniques, news and inspiration that I’ve come across this month. In this edition we discover stunning monochrome images taken underwater and learn the story of a pioneering aerial photographer from the 1920s. We look at a beautiful portrait series and see the incredible winners of the 2025 Nature Photographer of the Year Contest. So, with no further ado, I give you this month’s _Shadow & Light Monthly_. Go grab yourself a cuppa and enjoy this month’s selections below. Please let me know in the comments what you think. ## Pick of the Month – Matt Draper Held His Breath to Capture These Exceptional Underwater Photos © Matt Draper Matt Draper’s underwater photography, featured in his new exhibition _Within One Breath_ , is nothing short of stunning. He captures sharks, whales, and seals while freediving on a single breath. All shot in stunning black-and-white, lit only by the natural light of the ocean. What surprises me the most is that Draper shoots this work using a Leica rangefinder – a camera he himself has called “the hardest and most impractical camera I could have chosen to take underwater.” The manual focus rangefinder is a tricky beast to master but I can’t imagine how difficult it must be underwater. However, that choice seems to feed his artistry. He says the very act of making things harder – designing his own Sub13 underwater housing, diving on breath-hold – is part of his creative drive. He’s clearly someone who doesn’t like to take the easy route! The result is profoundly beautiful: the high contrast, the deep, rich blacks – I absolutely love how dark and crisp the tones are. Draper told PetaPixel that he’s “constantly chasing” those blacks, and when he gets them just right, “it’s magic.” To see more of Draper’s vision and read his reflections on craft, light, and his relationship with the sea, check out the full article on PetaPixel. ## Additional Reads ### This Daredevil Aerial Photographer From the 1920s Was Also a Photoshop Pioneer Alfred G. Buckham, Edinburgh, about 1920. National Galleries of Scotland. Purchased 1990. © Richard and John Buckham. Back in the 1920s, Alfred G. Buckham wasn’t just a fearless aviator – he took to the skies in open-cockpit biplanes and stood up mid-flight to make exposures (yes, really), famously tying one leg to the seat so he could lean out of the aircraft. But perhaps equally remarkable was his darkroom wizardry: using the early analogue equivalent of Photoshop, he would composite multiple glass negatives – especially sky and cloud images from his “cloud library” of over 2,000 plates – to create dreamlike aerial scenes. What he achieved makes me appreciate how different things are today. With drones, we can capture aerial views with ease, precision, and stability. But Buckham? He risked his life, flew with no harness and then laboured in the darkroom to build each picture piece by piece. His process was as much about imagination as it was about technical skill. I was particularly drawn to the image of Edinburgh Castle above because I asked my beautiful wife to marry me right there at the foot of the castle many years after this image was captured. For a deeper dive into his story, his aerial theatrics, and how his early composite work paved the way for modern techniques, read the full article on PetaPixel ### Where the Night Has No End! ©️ GMB Akash GMB Akash’s recent series _Where the Night Has No End_ feels deeply intimate and quietly powerful. The portraits, often bathed in soft night-light or shadow, use a restrained palette of colours to draw you into the vulnerability of his subjects. What strikes me most is how the muted tones and gentle warmth create a sense of closeness, while the darkness around them hints at hardship, loneliness, or unspoken stories. Akash is a Bangladeshi documentary photographer whose work focuses on people living on the margins of society. Over a career spanning decades, he has earned more than 100 international awards and exhibited worldwide. Through his lens, he brings dignity and emotional presence to lives often overlooked. His own words – from his blog – feel particularly resonant: “They share food when there is little. They wipe away each other’s tears. They carry each other through the hardest days… I jot down my heart’s language.” The empathy in that sentence is mirrored in his work – it’s not just social reportage, it’s a deeply human connection. To explore the full portraits and read more in his own voice, check out the series on GMB Akash’s blog ### Incredible Winners of the 2025 Nature Photographer of the Year Contest “Sundance” by Åsmund Keilen. Overall Winner and Winner, Birds. This stunning image, titled “Sundance” by Åsmund Keilen took the crown as the Overall Winner and the Birds category winner in the 2025 _Nature Photographer of the Year_. Taken just outside Oslo on a scorching summer day, the image emerged almost by accident: Keilen had left his coffee cup on the roof of his old blue Mercedes as he backed out of his driveway. Beside the spilled cup, he noticed tiny orange birch seeds that had fallen during the night. Above them, the reflecting sun and flitting shapes turned into dancing common swifts. Keilen used in-camera multiple exposure to recreate what he saw through his eyes: a kaleidoscopic impression of motion, light and reflection. He describes the moment beautifully: “Freedom seemed to take form in chaos.” I absolutely love this image – it feels dreamlike, atmospheric and poetic all at once. There’s something deeply emotional in the way the birds are silhouetted against the glowing sun, as though Keilen has captured not just a moment, but a feeling. It’s a reminder that some of the most powerful photographs come when you’re just present, open to wonder, and willing to follow where your eye leads. For a full look at Keilen’s work and more of the other winning images, read the original article on My Modern Met. ## Until Next Time… I hope you enjoy the articles above. Don’t forget you can follow my Shadow & Light magazine over on Flipboard if you’d like to see more of what I’m reading if you like what you’ve seen here. View my Flipboard Magazine. ## Shadow & Light Magazine _Shadow& Light_ is a list of curated photography stories, features, techniques, news and inspiration that I maintain on Flipboard. It’s a great way to create myself a ‘read later’ list. Feel free to follow the magazine for updates or keep an eye on my blog where I regularly post Shadow & Light monthly highlights.

Previously unavailable to US overlanders, ARB's inspirational Earth Camper finally makes its way to US roads — and off them, too.

The uniquely vulnerable West Antarctic Ice Sheet holds enough water to raise global sea levels by 5 meters. But when that will happen — and how fast — is anything but settled.

This star-studded, instant classic political thriller feels a little too relevant in this moment.

Activists, residents and elected leaders say increasingly combative tactics used by federal immigration agents are sparking violence and fueling neighborhood tensions in the nation’s third-largest city.

A duo of Tesla shareholder-influencers tried to complete Elon Musk’s coast-to-coast self-driving ride that he claimed Tesla would be able...

NASA is finally releasing details on its discovery of Mars biosignatures and exactly what that means for alien life.

President Donald Trump says he's firing Federal Reserve Governor Lisa Cook, a sharp escalation in his battle to exert greater control over what has long been considered an institution independent from day-to-day politics.

Each of SpaceX's enormous Starship explosions is costing the private space company an enormous amount of money.

The problem with arguing that neoliberals left American workers behind is that it’s mostly untrue.

Spread the love Leica was among Fujifilm, Canon, and Sigma, which have declared the increase in prices of gear due to Donald Trump’s declaration of tariffs. While the company didn’t reveal how much the prices will grow, there is now a clear indication that the company has seen both a minor and major increase in the prices of gear. Leica equipment is already expensive, but with the new announcement, this only adds to the challenges of rising prices of cameras and lenses. According to L-Rumors, we have seen the price of a few cameras, which are largely made in Germany, with one created in China. As a result, the latter saw a far higher hike than other models: * Leica D-Lux 8: The camera saw a 90% price increase, going from $1,595 to $2,790, as it is made in China. * Leica M11 Monochrome: Only a 10% price increase from $9,195 to $10,160. * Leica M11-D: Saw a 7% price rise from $9,195 to $9,839. * Leica M11-P: a 7% rise from $9,195 to the new price of $9,840. * Leica SL3: Also noticed a 7% price hike from $6,995 to $7,485. * Leica Q3: Saw about a $12% rise, as the original was $6000, but now it costs $6,735. * Leica Q3 43: Saw a 7% rise from $6,895 to $7,380. * Leica SL3s: Also noticed a 7% increase from $5,295 to $5,665. * Vario-Elmarit-SL 70-200mm f/2.8 ASPH: A 7% increase from $3,295 to $3,525. * APO-Summicron-SL 35mm f/2 ASPH: Also a 7% increase from $5195 to $5,560. * Super-Vario-Elmar-SL 16-35mm f/3.5-4.5 ASPH: A 24% increase from $5,495 to $6,845. * APO-Vario-Elmarit-SL 90-280mm f2.8-4: A 22% increase from $6395 to $7,805. * Vario-Elmarit-SL 24-90mm f/2.8-4 ASPH: A 14% increase from $5,495 to $6,310. * Vario-Elmar-SL 100-400mm f/5-6.3 lens: An 11% increase from $2,195 to $2,455. From the looks of it, some cameras and lenses have seen a less than 10% increase, with a few going above 15%. This is particularly visible in the case of zoom lenses, with the Leica 16-35mm seeing a 24% rise. We aren’t sure what the reason is behind this, but our best guess would be the inclusion of imported parts, which may or may not have been created in China. Other than that, it is unclear as to why zoom lenses alone would see a bigger shift in price. Either way, companies like Leica have found ways to ensure that the price hike is not too significant, otherwise, some may delay their launch. But a hike has been inevitable. In addition, it remains unclear what Donald Trump may announce after the 90-day pause, as that means Leica may face a 20% tariff, which was originally suggested by the President. However, if Europe and China can both barter a deal, the prices may stay the same, which is still better than an additional hike. Leica’s legacy is built on the creation of cameras that can last a lifetime, and their after-sales service is just as great. As a result, some photographers do not mind paying an additional few thousand, if it means they get a camera that can last for more than a decade or two. But even then, some may face a challenge, since this means that luxury cameras may become unachievable. **_Edit: After much debate, the United States and China have announced a new 90-day reduction in tariffs on April 12. The US has a 30% tariff on Chinese goods, which was initially 145%, while China will tax the U.S.-imported goods at 10%, from 125% as previously announced. The development was announced following the price hike from Leica._** leica Leica APO-Summicron-SL 35mm f/2 ASPH Leica APO-Vario-Elmarit-SL 90-280mm f2.8-4 leica d-lux 8 leica m11 monochrome leica m11-d leica m11-p Leica Q3 leica q3 43 leica sl3 leica sl3s Leica Super-Vario-Elmar-SL 16-35mm f/3.5-4.5 ASPH Leica Vario-Elmar-SL 100-400mm f/5-6.3 Leica Vario-Elmarit-SL 24-90mm f/2.8-4 ASPH Leica Vario-Elmarit-SL 70-200mm f/2.8 ASPH price hike Tariffs Shares Previous Post ### How to Avoid Paying for a Camera Repair

Spread the love The beauty of using vintage cameras is not just in the images that they provide you, but the way the devices feel in your hand. The knobs, buttons, lever, and shutter sound can make your shooting experience even more engaging, while allowing you savor the moments as they come by. If you are a film photographer looking for exceptional vintage cameras, we bring to you a few of our tested devices, which will make your creative journey more exciting. Let’s dig in. ## Mamiya RB67 Pro-S Mamiya RB67 Pro-S A 6×7 medium format analog camera, the Mamiya RB67 Pro-S is a fully manual camera that allows you to shoot 120 film. This means the device is perfect for serious portraiture, studio, and landscape works, allowing you to become immersed in the details of the scene. There is no light meter built-in, while the aperture and shutter controls (up to 1/400 sec) are on the lens. Some of the things we enjoyed are the lens, the bright viewfinder, the built-in, and precise focusing. buy now ## Pentax 67 Pentax 67 One of the most drooled-over vintage cameras, the Pentax 67 is a medium format device that shoots 120 or 220 film rolls. It also features a leaf shutter, a flash button, and we tested this with Pentax 45mm f4 and 105mm f2.4 lenses. The camera is also portable, has a good lens lineup, good diopters, various finders, and great depth of field preview. The leaf shutter makes it easy for a fast flash sync of 1/30th. Since it’s small, it makes it easy to shoot outdoors. buy now ## Bronica ETRS Bronica ETRS The Bronica ETRS has a very different way of shooting. The camera allows both a non-metered waist-level finder and a standard shutter release, and one can shoot between 1/500 of a second to 8 seconds. There is a leaf shutter, and you can use Slow film stocks, narrow apertures, or ND filters for daytime shoots. There is also a button for batteries, so you can check if your camera will run out of battery soon. As we said, “On the whole, images coming out of this camera-and-lens combo are just beautiful, with that quintessential film look about them and nice subject isolation at wider apertures, where the system performs impressively.” The slow camera is ideal for artistic work and perhaps some memorable portraits. buy now ## Leica M4-P Leica M4-P If you talk about vintage cameras, you can’t leave Leica behind. The Leica M4-P is designed for professional photographers (as the P suggests), and it was designed in Canada, rather than Germany. The M4P has .72 magnification frames, seen in the Leica M6, and it was created from 1980 to 1986. It also lacks a light meter and can shoot at 3 fps. As we said in our review: “If you want to have the widest variety of frame lines per your favorite focal lengths, if you want a very reliable camera, if you want a number of shutter speeds, and if you want a Leica M mount camera with a great viewfinder, then there is very little that can beat the Leica M4-P.” Why select this over the Leica M6? Well, when the electronics in the Leica M6 break, it basically becomes a Leica M4. So why not just go for the analog version to begin with? buy now ## Pentacon Six TL Pentacon Six TL One of the few vintage cameras called “SLR on steroids”, the Pentacon Six TL rivals Pentax 67. It shoots 6×6 frames, has a top viewfinder, and to advance the film, you have to turn the lever a total of 360 degrees. To test the camera, we used the Carl Zeiss 80mm f2.8, which worked wonderfully well for portraits. What you get is good square format images, a bright and accurate viewfinder, good for outdoor shoots, and the build quality is exceptional. However, the camera’s biggest challenge is loading and advancing the film, which requires patience. buy now analog cameras Cameras film photography medium format vintage cameras Shares Previous Post ### This Powerful Exhibit Sheds Light on 35 Years of Working Class Realities

Support us on Patreon » Though the original promise of the internet has been twisted and distorted, today we’re seeing more and more people working to restore decentralization and …

Erin and I stood at the front of the room, our seven-minute pitch slides for Known still projected above us. At the wooden table in front of us, investors and media executives prepared to give us unfiltered feedback about what we’d just presented to them. Beyond them, an audience of entrepreneurs, more investors, and other enthusiasts were raising their hands. “Does your excitement outweigh your hesitations?” Corey Ford asked the Matter audience. A spattering of hands shot up; most of the audience did not raise theirs. At Matter, Design Reviews were a big deal: a structured, safe way to find out what investors and potential customers actually thought about your business. You would pitch; then the audience would vote on a handful of questions; then the panel would weigh in. Corey took a beat before asking his next question, microphone in hand. “Does this venture have the potential to change media for good?” A few more hands shot up this time. “Does this venture have the potential to raise investment? If not, does it have the potential to raise alternative funding?” No hands. The panel eviscerated us. I’d started writing the first version of Known while my mother recovered from her double lung transplant. My mother wanted people to talk to about her experiences, but she didn’t trust the likes of Facebook to host those conversations. I’d built the platform to provide an alternative. I cared about the platform deeply; I cared about the idea of communities that didn’t yield their data to one of a handful of centralized services even more. Indieweb and open social web people seemed excited. But I couldn’t tell the story in a way that resonated with people who weren’t a part of those worlds. This was 2014, before Cambridge Analytica or the genocide in Myanmar. The most common question I was asked was, “what’s wrong with Facebook?” A decade later, nobody’s asking that question. We’ve all seen what’s wrong. The centralized social web has failed us; its owners treat their platforms as a way to spread propaganda and further entrench their power, often at the expense of democracy. Mark Zuckerberg likens himself to a Roman emperor even while his policies fail community after community. Under Elon Musk, X has been reinvented as a firehose of toxicity. Users are hungry for alternatives. In my previous posts in this series, I discussed what I would do if I ran Bluesky and Mastodon. But now let’s zoom out: what if I started fresh? There are several ways you could approach building a new open social web platform. You could hope to be remembered for building a great open protocol, as Tim Berners-Lee is, but I believe today’s need is more acute. Few people were asking for the web in 1989; it emerged anyway, changing peoples’ minds, habits, and culture. For its first decade, it was a slow-burning movement. In 2025, great harms are being done to vulnerable communities, and the profits from centralized platforms are used in part to fuel global fascism. Building a great protocol isn’t enough to get us where we need to go. We need to adopt a different mindset: one of true service, where we build an alternative _to serve people’s direct needs today_. I think these principles are important: * Any new product must be laser-focused on solving people’s needs. The technical details — protocols, languages, architecture, approach — are all in service of creating a great solution to real human problems. * The perfect can never be allowed to obstruct the good. Ideological purity is next to impossible. The important thing is to build something that’s better than what we have today, and continue iterating towards greatness. * Everyone who works on such a platform must be able to make a good living doing so. Or to put it another way, nobody should be financially penalized for working on the open social web. * The platform must be sustainable. If you’re making something people rely on, you owe it to them to ensure it can last. In his post Town squares, backyards, better metaphors, and decentralised networks, Anders Thoresson points out that social _media_ and social _networks_ are two different things that have sometimes been conflated. Social media is the proverbial global town square. A social network is the web of relationships between people; these might span apps, the web, and in-person conversations alike. As I wrote in my 2008 piece The Internet is people: > Let’s reclaim a piece of language: a social network is an interconnected system of people, as I’ve suggested above. The websites that foster social networks are simply social networking tools. A social network doesn’t live on the Web, but a website can help its members communicate and share with each other. I believe there’s enormous value to be found in building new platforms to support social networks in particular. The goal shouldn’t be to try and gather everyone in the world around a particular voice or algorithmic spectacle, as X now does with Elon Musk’s account and ideas; it should be to support networks of people and help them connect with each other on their terms. From the same piece: > The idea of a social networking tool is to make that network communicate more efficiently, so anything that the tool does should make it easier for that network to talk to each other and share information. The tool itself shouldn’t attempt to create the network – although that being said, new network connections may arise through a purpose. Most of us have made new contacts on Flickr or Twitter, for example, because we enjoyed someone’s content. Compare and contrast with Meta’s latest strategy to fill its platforms with AI-generated users, _literally_ creating the network. If I were starting from scratch — grounded in these principles, and committed to serving real human networks — here’s what I’d build. As I hinted at in my if I ran Mastodon piece, I believe there is a need for a private-by-default, federated platform designed for groups that already know each other or are actively building trust. Think mutual aid groups, local advocacy orgs, artist collectives, parent groups, cooperatives, or even small media orgs with deeply engaged communities. On this platform, anyone can build a group with its own look and feel, set of features, rules, and norms. As a user, I can join any number of groups with a single account, and read updates on a dashboard where I can easily switch between types of content (long-form vs short-form), modes of engagement (conversations vs published pieces), and categories (topics, timely updates vs evergreen). Because it embraces the open social web, a user can connect to these groups using any compatible profile, and if a user doesn’t like the dashboard that the platform provides, perhaps because they don’t like how it prioritizes or filters content, they can choose another one made by someone else. Over time, groups can be hosted by multiple platform providers — and users will still be able to interact, collaborate, and share content as if they were on the same system. Let’s say I’m part of three very different communities: a neighborhood mutual aid group, a nonprofit newsroom, and a writing collective. On this platform, each has its own space, with its own tone, style, and boundaries. The local mutual aid group uses their space to coordinate grocery drop-offs, ride shares, and emergency needs. Everything is private, and posts are tagged by urgency. There’s a shared resource library and a microblogging space for check-ins. Members can signal availability without having to explain. The newsroom uses its space to share behind-the-scenes updates with engaged readers, collect community tips, and publish previews of investigations. It connects directly with their existing WordPress site and lets audience editors manage conversations without needing a developer. The writing collective is weird and messy and fun. It has a public-facing stream of essays and poetry, but also a rotating “writing prompt room” and a long-form thread space that acts like a slow-moving group zine. It’s run as a co-op, and contributors vote on changes to how it’s governed. The writing is mostly private for its members, but every so often the group makes a piece available for the outside world. Each of these groups lives in its own lane and can be accessed individually on the web, but I choose to keep up to date on all of them from a dashboard that reflects how I think and what I care about. I can configure it, but it also learns from my use over time, and even suggests new groups that I might want to be a part of. It also lets me search for people I know or ideas I want to hear more about and surfaces groups relevant to both. The dashboard is available on the web and as a clean, responsive mobile app with a best-in-class consumer-grade design. Because it’s all built on the open social web, I can take my identity and content with me if I ever leave. If there’s a dashboard by another company that works better for me (or fits my ideals better, for example by _not_ learning from my use automatically), I can switch to it seamlessly. If I want, I can move my profile and memberships to an account hosted by another provider. Even if I don’t do those things, I can connect other apps to my account that give me new insights about the content and conversations I’m interested in — for example to highlight breaking news stories, surface group events I might be interested in, or to give me extra moderation powers for communities I run. Here’s the bit that might make open social web purists upset: all of this would be built by a for-profit public benefit company and run as a hosted service. At launch, there would be no open source component. Gasp! I can already read the Mastodon replies to this post. But rather than a betrayal of open social web values, I see these things as a way to better support the needs of the platform and the values of the space. This isn’t about profit above all else. It’s about aligning incentives to support a healthy, values-driven product, and making that alignment resilient over time. (Don’t worry, I’ll get back to open source below.) So far, most open source self-hosted platforms have prioritized engineering efforts. Resources haven’t been available for researchers, designers, trust and safety teams, or for dedicated staff to foster partnerships with other projects. Those things aren’t nice-to-haves: they’re vital for any service to ensure that it is fit for purpose for its users, a delightful experience to use, and, crucially for any social platform, safe for vulnerable users to participate in. Building a financial model in from the start improves the chances of those things being available. If we want great design, we need to pay designers. If we want a safe, healthy community, we need to pay a trust and safety team. And so on. In order to pay for the teams that make it valuable, the platform will charge for non-core premium features like SSO and integrations, offer a hands-on enterprise concierge service, and take a cut from marketplace transactions inside groups. Most importantly, the business model isn’t based on reach, surveillance, or ads; the values of the business are aligned with the communities it hosts. In its earliest stages, every platform needs to reduce the feedback loop between its users and builders as much as possible. Incubating it internally until the basic interaction models, look and feel, and core feature-set are right will allow that to happen faster. I’ve found in the past that open source communities can muddy that feedback loop in the earliest stages of a project: there are people who will cheerlead something because it’s open source and not because the product works for them in itself. There are also other people who will relentlessly ask for esoteric features that benefit only them — or will be abusive or disrespectful in the open source community itself. None of these is what you want if your focus is on building something useful. Finally, something happens when you release a project under an open source license: anyone can use it. It’s a permissive ethos that sits at the core of the movement, but it also has a key downside for open source social platforms: someone may take a platform you’ve put a great deal of work into and use it for harm. There is nothing to stop someone from taking your code and using it to support Nazis, child abuse, or to organize other kinds of real-world violence. In contrast, a hosted product can be vigilant and remove those communities. By not releasing an open source project _at first_ , the business has a chance to seed the culture of the platform. It can provide the resources, support, and vigilance needed to make sure the space is inclusive, respectful, and safe. Once the platform has matured and there are thriving, healthy communities, that’s when we can release a reference codebase — not as a symbolic gesture, but as a foundation others can build on without compromise. That moment would come once the platform has proven its core use case, the community culture is thriving, and the financial base is strong enough to support long-term governance. In the meantime, because it’s all based on open social web protocols, other developers could have been building their own participating open source community platforms, dashboards, and libraries. Last thing: I haven’t mentioned _where_ I would run this from. Vulnerable communities are under attack in many parts of the world, notably the US, and it isn’t clear that data will be safe from subpoenas or other legal threats. So the business would be headquartered in Switzerland, a traditional home for neutral parties and a jurisdiction that offers stronger protections for user data. While starting it would require raising investment — and, perhaps, grants for starting a mission-driven high-tech business from Switzerland, the EU, and elsewhere — it would not aim to be a venture-scale business, and would operate largely independently from the US tech ecosystem. It would inclusively hire talent from all over the world and offer hybrid work: remotely but with the opportunity to come to Zurich and collaborate in-person as the need arose. It would, of course, be a business that invested heavily in DEI, with strong benefits. These policies would allow a more diverse staff to collaborate on building it, ensuring that a greater array of perspectives were involved in its design. This isn’t just morally correct: along with the choice of location and business model, it represents a commitment to resilience. Resilience, I hope you’ll agree, is something we need in abundance. I began this series by asking how I’d run someone else’s platform. But the real question is: what should we build now, and how do we build it together? What are the mindsets that will provide a true alternative? And how can we ensure it succeeds? If any of this resonates, I’d love to chat. You can always email me at ben@werd.io or on Signal at benwerd.01. _Previously in this series:if I ran Bluesky Product and if I ran Mastodon. Subscribe to get every post via email._ _Photo byRenzo D'souza on __Unsplash_

Over the years, I've had a bunch of ideas on how to move the Fediverse forward. This article highlights the culmination of what I'd like to build.

Artificial intelligence is a broad term encompassing many different subtypes, from apps that can write poetry to algorithms that are able to spot patterns that would otherwise get missed – and now AI modeling has just played a major role in an Alzheimer's study. Researchers from the University of California, San Diego (UC San Diego) used AI to discover that a gene recognized as a sign of Alzheimer's disease could be causing it too. It highlights one of the big challenges in the study of Alzheimer's: understanding both the changes the disease causes, and the changes that cause the disease. An enzyme called phosphoglycerate dehydrogenase (PHGDH), and the gene that encodes it, were the focus here. The researchers had previously established the gene was typically more active in people with faster-progressing Alzheimer's. The new study looked at the influence of the PHGDH gene. (Zhong lab) What wasn't clear was what was driving this link. The team used AI to model the structure of the PHGDH enzyme more fully, suggesting it had a previously hidden function: flicking switches for other specific genes on and off. Further analysis showed PHGDH interacting with two genes inside brain cells known as astrocytes, in ways that interfere with the brain's ability to regulate inflammation and clear out waste. The researchers think this could be one of the tipping points triggering Alzheimer's, and explaining the association between PHGDH and the disease. "It really demanded modern AI to formulate the three-dimensional structure very precisely to make this discovery," says bioengineer Sheng Zhong, from UC San Diego. Next, the team investigated ways to inhibit PHGDH, but only partly – ideally, a drug would block its ability to regulate genes in astrocytes, while still allowing it to perform its vital enzymatic role. The team found a molecule called NCT-503 that fit the bill. AI modeling was deployed again to examine the structure of this molecule, and how it interacts with PHGDH. NCT-503 seems to bind to a pocket in PHGDH to stop its unauthorized gene-switching. There's still a long way to go before an actual Alzheimer's drug might be developed from this finding, but the research has shown that a treatment based on NCT-503 can put up guardrails around PHGDH in mouse models of the disease. The mice that were treated showed improvements in memory and anxiety tests. "Now there is a therapeutic candidate with demonstrated efficacy that has the potential of being further developed into clinical tests," says Zhong. "There may be entirely new classes of small molecules that can potentially be leveraged for development into future therapeutics." Crucially, NCT-503 is able to pass the blood-brain barrier to access neurons and their associated cells, making the new treatment research even more promising. Drugs based on the molecule could even be taken orally. While it's taking time to unpick the complexities of Alzheimer's disease, and all the different factors involved in its development – from environmental stresses to inherited genetics – each new study gets us a step closer to solutions, and improving how we tackle the condition. "Unfortunately, treatment options for Alzheimer's disease are very limited," says Zhong. "And treatment responses are not outstanding at this moment." The research has been published in _Cell_.