Last year, MACK Books published Architecture from Below, which anthologized writings by the French Brazilian architect, theorist, and painter Sérgio Ferro. (Douglas Spencer reviewed it for AN.) Now, MACK follows with Design and the Building Site and Complementary Essays, the second in the trilogy of books dedicated to Ferro’s scholarship. The following excerpt of the author’s 2023 preface to the English edition, which preserves its British phrasing, captures Ferro’s realization about the working conditions of construction sites in Brasília. The sentiment is likely relatable even today for young architects as they discover how drawings become buildings. Design and the Building Site and Complementary Essays will be released on May 22. If I remember correctly, it was in 1958 or 1959, when Rodrigo and I were second- or third year architecture students at FAUUSP, that my father, the real estate developer Armando Simone Pereira, commissioned us to design two large office buildings and eleven shops in Brasilia, which was then under construction. Of course, we were not adequately prepared for such an undertaking. Fortunately, Oscar Niemeyer and his team, who were responsible for overseeing the construction of the capital, had drawn up a detailed document determining the essential characteristics of all the private sector buildings. We followed these prescriptions to the letter, which saved us from disaster. Nowadays, it is hard to imagine the degree to which the construction of Brasilia inspired enthusiasm and professional pride in the country’s architects. And in the national imagination, the city’s establishment in the supposedly unpopulated hinterland evoked a re-founding of Brazil. Up until that point, the occupation of our immense territory had been reduced to a collection of arborescent communication routes, generally converging upon some river, following it up to the Atlantic Ocean. Through its ports, agricultural or extractive commodities produced by enslaved peoples or their substitutes passed towards the metropolises; goods were exchanged in the metropolises for more elaborate products, which took the opposite route. Our national identity was summed up in a few symbols, such as the anthem or the flag, and this scattering of paths pointing overseas. Brasilia would radically change this situation, or so we believed. It would create a central hub where the internal communication routes could converge, linking together hithertoseparate junctions, stimulating trade and economic progress in the country’s interior. It was as if, for the first time, we were taking care of ourselves. At the nucleus of this centripetal movement, architecture would embody the renaissance. And at the naval of the nucleus, the symbolic mandala of this utopia: the cathedral. Rodrigo and I got caught up in the euphoria. And perhaps more so than our colleagues, because we were taking part in the adventure with ‘our’ designs. The reality was very different — but we did not know that yet. At that time, architects in Brazil were responsible for verifying that the construction was in line with the design. We had already monitored some of our first building sites. But the construction company in charge of them, Osmar Souza e Silva’s CENPLA, specialized in the building sites of modernist architects from the so-called Escola Paulista led by Vilanova Artigas (which we aspired to be a part of, like the pretentious students we were). Osmar was very attentive to his clients and his workers, who formed a supportive and helpful team. He was even more careful with us, because he knew how inexperienced we were. I believe that the CENPLA was particularly important in São Paulo modernism: with its congeniality, it facilitated experimentation, but for the same reason, it deceived novices like us about the reality of other building sites. Consequently, Rodrigo and I travelled to Brasilia several times to check that the constructions followed ‘our’ designs and to resolve any issues. From the very first trip, our little bubble burst. Our building sites, like all the others in the future capital, bore no relation to Osmar’s. They were more like a branch of hell. A huge, muddy wasteland, in which a few cranes, pile drivers, tractors, and excavators dotted the mound of scaffolding occupied by thousands of skinny, seemingly exhausted wretches, who were nevertheless driven on by the shouts of master builders and foremen, in turn pressured by the imminence of the fateful inauguration date. Surrounding or huddled underneath the marquees of buildings under construction, entire families, equally skeletal and ragged, were waiting for some accident or death to open up a vacancy. In contact only with the master builders, and under close surveillance so we would not speak to the workers, we were not allowed to see what comrades who had worked on these sites later told us in prison: suicide abounded; escape was known to be futile in the unpopulated surroundings with no viable roads; fatal accidents were often caused by weakness due to chronic diarrhoea, brought on by rotten food that came from far away; outright theft took place in the calculation of wages and expenses in the contractor’s grocery store; camps were surrounded by law enforcement. I repeat this anecdote yet again not to invoke the benevolence of potential readers, but rather to point out the conditions that, in my opinion, allowed two students (Flávio Império joined us a little later) still in their professional infancy to quickly adopt positions that were contrary to the usual stance of architects. As the project was more Oscar Niemeyer’s than it was our own, we did not have the same emotional attachment that is understandably engendered between real authors and their designs. We had not yet been imbued with the charm and aura of the métier. And the only building sites we had visited thus far, Osmar’s, were incomparable to those we discovered in Brasilia. In short, our youthfulness and unpreparedness up against an unbearable situation made us react almost immediately to the profession’s satisfied doxa. Unprepared and young perhaps, but already with Marx by our side. Rodrigo and I joined the student cell of the Brazilian Communist Party during our first year at university. In itself, this did not help us much: the Party’s Marxism, revised in the interests of the USSR, was pitiful. Even high-level leaders rarely went beyond the first chapter of Capital. But at the end of the 1950s, the effervescence of the years to come was already nascent:  […] this extraordinary revival […] the rediscovery of Marxism and the great dialectical texts and traditions in the 1960s: an excitement that identifies a forgotten or repressed moment of the past as the new and subversive, and learns the dialectical grammar of a Hegel or an Adorno, a Marx or a Lukács, like a foreign language that has resources unavailable in our own. And what is more: the Chinese and Cuban revolutions, the war in Vietnam, guerrilla warfare of all kinds, national liberation movements, and a rare libertarian disposition in contemporary history, totally averse to fanaticism and respect for ideological apparatuses of (any) state or institution. Going against the grain was almost the norm. We were of course no more than contemporaries of our time. We were soon able to position ourselves from chapters 13, 14, and 15 of Capital, but only because we could constantly cross-reference Marx with our observations from well-contrasted building sites and do our own experimenting. As soon as we identified construction as manufacture, for example, thanks to the willingness and even encouragement of two friends and clients, Boris Fausto and Bernardo Issler, I was able to test both types of manufacture — organic and heterogeneous — on similar-sized projects taking place simultaneously, in order to find out which would be most convenient for the situation in Brazil, particularly in São Paulo. Despite the scientific shortcomings of these tests, they sufficed for us to select organic manufacture. Arquitetura Nova had defined its line of practice, studies, and research. There were other sources that were central to our theory and practice. Flávio Império was one of the founders of the Teatro de Arena, undoubtedly the vanguard of popular, militant theatre in Brazil. He won practically every set design award. He brought us his marvelous findings in spatial condensation and malleability, and in the creative diversion of techniques and material—appropriate devices for an underdeveloped country. This is what helped us pave the way to reformulating the reigning design paradigms.  We had to do what Flávio had done in the theatre: thoroughly rethink how to be an architect. Upend the perspective. The way we were taught was to start from a desired result; then others would take care of getting there, no matter how. We, on the other hand, set out to go down to the building site and accompany those carrying out the labor itself, those who actually build, the formally subsumed workers in manufacture who are increasingly deprived of the knowledge and know-how presupposed by this kind of subsumption. We should have been fostering the reconstitution of this knowledge and know-how—not so as to fulfil this assumption, but in order to reinvigorate the other side of this assumption according to Marx: the historical rebellion of the manufacture worker, especially the construction worker. We had to rekindle the demand that fueled this rebellion: total self-determination, and not just that of the manual operation as such. Our aim was above all political and ethical. Aesthetics only mattered by way of what it included—ethics. Instead of estética, we wrote est ética [this is ethics]. We wanted to make building sites into nests for the return of revolutionary syndicalism, which we ourselves had yet to discover. Sérgio Ferro, born in Brazil in 1938, studied architecture at FAUUSP, São Paulo. In the 1960s, he joined the Brazilian communist party and started, along with Rodrigo Lefevre and Flávio Império, the collective known as Arquitetura Nova. After being arrested by the military dictatorship that took power in Brazil in 1964, he moved to France as an exile. As a painter and a professor at the École Nationale Supérieure d’Architecture de Grenoble, where he founded the Dessin/Chantier laboratory, he engaged in extensive research which resulted in several publications, exhibitions, and awards in Brazil and in France, including the title of Chevalier des Arts et des Lettres in 1992. Following his retirement from teaching, Ferro continues to research, write, and paint.

June 13, 20253 min readCould Iran Have Been Close to Making a Nuclear Weapon? Uranium Enrichment ExplainedWhen Israeli aircraft recently struck a uranium-enrichment complex in the nation, Iran could have been days away from achieving “breakout,” the ability to quickly turn “yellowcake” uranium into bomb-grade fuel, with its new high-speed centrifugesBy Deni Ellis Béchard edited by Dean VisserMen work inside of a uranium conversion facility just outside the city of Isfahan, Iran, on March 30, 2005. The facility in Isfahan made hexaflouride gas, which was then enriched by feeding it into centrifuges at a facility in Natanz, Iran. Getty ImagesIn the predawn darkness on Friday local time, Israeli military aircraft struck one of Iran’s uranium-enrichment complexes near the city of Natanz. The warheads aimed to do more than shatter concrete; they were meant to buy time, according to news reports. For months, Iran had seemed to be edging ever closer to “breakout,” the point at which its growing stockpile of partially enriched uranium could be converted into fuel for a nuclear bomb. (Iran has denied that it has been pursuing nuclear weapons development.)But why did the strike occur now? One consideration could involve the way enrichment complexes work. Natural uranium is composed almost entirely of uranium 238, or U-238, an isotope that is relatively “heavy” (meaning it has more neutrons in its nucleus). Only about 0.7 percent is uranium 235 (U-235), a lighter isotope that is capable of sustaining a nuclear chain reaction. That means that in natural uranium, only seven atoms in 1,000 are the lighter, fission-ready U-235; “enrichment” simply means raising the percentage of U-235.U-235 can be used in warheads because its nucleus can easily be split. The International Atomic Energy Agency uses 25 kilograms of contained U-235 as the benchmark amount deemed sufficient for a first-generation implosion bomb. In such a weapon, the U-235 is surrounded by conventional explosives that, when detonated, compress the isotope. A separate device releases a neutron stream. (Neutrons are the neutral subatomic particle in an atom’s nucleus that adds to their mass.) Each time a neutron strikes a U-235 atom, the atom fissions; it divides and spits out, on average, two or three fresh neutrons—plus a burst of energy in the form of heat and gamma radiation. And the emitted neutrons in turn strike other U-235 nuclei, creating a self-sustaining chain reaction among the U-235 atoms that have been packed together into a critical mass. The result is a nuclear explosion. By contrast, the more common isotope, U-238, usually absorbs slow neutrons without splitting and cannot drive such a devastating chain reaction.On supporting science journalismIf you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.To enrich uranium so that it contains enough U-235, the “yellowcake” uranium powder that comes out of a mine must go through a lengthy process of conversions to transform it from a solid into the gas uranium hexafluoride. First, a series of chemical processes refine the uranium and then, at high temperatures, each uranium atom is bound to six fluorine atoms. The result, uranium hexafluoride, is unusual: below 56 degrees Celsius (132.8 degrees Fahrenheit) it is a white, waxy solid, but just above that temperature, it sublimates into a dense, invisible gas.During enrichment, this uranium hexafluoride is loaded into a centrifuge: a metal cylinder that spins at tens of thousands of revolutions per minute—faster than the blades of a jet engine. As the heavier U-238 molecules drift toward the cylinder wall, the lighter U-235 molecules remain closer to the center and are siphoned off. This new, slightly U-235-richer gas is then put into the next centrifuge. The process is repeated 10 to 20 times as ever more enriched gas is sent through a series of centrifuges.Enrichment is a slow process, but the Iranian government has been working on this for years and already holds roughly 400 kilograms of uranium enriched to 60 percent U-235. This falls short of the 90 percent required for nuclear weapons. But whereas Iran’s first-generation IR-1 centrifuges whirl at about 63,000 revolutions per minute and do relatively modest work, its newer IR-6 models, built from high-strength carbon fiber, spin faster and produce enriched uranium far more quickly.Iran has been installing thousands of these units, especially at Fordow, an underground enrichment facility built beneath 80 to 90 meters of rock. According to a report released on Monday by the Institute for Science and International Security, the new centrifuges could produce enough 90 percent U-235 uranium for a warhead “in as little as two to three days” and enough for nine nuclear weapons in three weeks—or 19 by the end of the third month.

The nuclei of atoms are often portrayed as round in textbooks, but it turns out they're rarely spherical.

It’s been more than two decades since scientists finished sequencing the human genome, providing a comprehensive map of human biology that has since accelerated progress in disease research and personalized medicine. Thanks to that endeavor, we know that each of us has about 20,000 protein-coding genes, which serve as blueprints for the diverse protein molecules that give shape to our cells and keep them functioning properly.Yet, we know relatively little about how those proteins are organized within cells and how they interact with each other, says Trey Ideker, a professor of medicine and bioengineering at University of California San Diego. Without that knowledge, he says, trying to study and treat disease is “like trying to understand how to fix your car without the shop manual.” Mapping the Human CellIn a recent paper in the journal Nature, Ideker and his colleagues presented their latest attempt to fill this information gap: a fine-grained map of a human cell, showing the locations of more than 5,000 proteins and how they assemble into larger and larger structures. The researchers also created an interactive version of the map. It goes far beyond the simplified diagrams you may recall from high school biology class. Familiar objects like the nucleus appear at the highest level, but zooming in, you find the nucleoplasm, then the chromatin factors, then the transcription factor IID complex, which is home to five individual proteins better left nameless. This subcellular metropolis is unintelligible to non-specialists, but it offers a look at the extraordinary complexity within us all.Surprising Cell FeaturesEven for specialists, there are some surprises. The team identified 275 protein assemblies, ranging in scale from large charismatic organelles like mitochondria, to smaller features like microtubules and ribosomes, down to the tiny protein complexes that constitute “the basic machinery” of the cell, as Ideker put it. “Across all that,” he says, “about half of it was known, and about half of it, believe it or not, wasn't known.” In other words, 50 percent of the structures they found “just simply don't map to anything in the cell biology textbook.”Multimodal Process for Cell MappingThey achieved this level of detail by taking a “multimodal” approach. First, to figure out which molecules interact with each other, the researchers would line a tube with a particular protein, called the “bait” protein; then they would pour a blended mixture of other proteins through the tube to see what stuck, revealing which ones were neighbors.Next, to get precise coordinates for the location of these proteins, they lit up individual molecules within a cell using glowing antibodies, the cellular defenders produced by the immune system to bind to and neutralize specific substances (often foreign invaders like viruses and bacteria, but in this case homegrown proteins). Once an antibody found its target, the illuminated protein could be visualized under a microscope and placed on the map. Enhancing Cancer ResearchThere are many human cell types, and the one Ideker’s team chose for this study is called the U2OS cell. It’s commonly associated with pediatric bone tumors. Indeed, the researchers identified about 100 mutated proteins that are linked to this childhood cancer, enhancing our understanding of how the disease develops. Better yet, they located the assemblies those proteins belong to. Typically, Ideker says, cancer research is focused on individual mutations, whereas it’s often more useful to think about the larger systems that cancer disrupts. Returning to the car analogy, he notes that a vehicle’s braking system can fail in various ways: You can tamper with the pedal, the calipers, the discs or the brake fluid, and all these mechanisms give the same outcome.Similarly, cancer can cause a biological system to malfunction in various ways, and Ideker argues that comprehensive cell maps provide an effective way to study those diverse mechanisms of disease. “We've only understood the tip of the iceberg in terms of what gets mutated in cancer,” he says. “The problem is that we're not looking at the machines that actually matter, we're looking at the nuts and bolts.”Mapping Cells for the FutureBeyond cancer, the researchers hope their map will serve as a model for scientists attempting to chart other kinds of cells. This map took more than three years to create, but technology and methodological improvements could speed up the process — as they did for genome sequencing throughout the late 20th century — allowing medical treatments to be tailored to a person’s unique protein profile. “We're going to have to turn Moore's law on this,” Ideker says, “to really scale it up and understand differences in cell biology […] between individuals.”This article is not offering medical advice and should be used for informational purposes only.Article SourcesOur writers at Discovermagazine.com use peer-reviewed studies and high-quality sources for our articles, and our editors review for scientific accuracy and editorial standards. Review the sources used below for this article:Cody Cottier is a contributing writer at Discover who loves exploring big questions about the universe and our home planet, the nature of consciousness, the ethical implications of science and more. He holds a bachelor's degree in journalism and media production from Washington State University.

The big Clair Obscur: Expedition 33 interview: Sandfall and Kepler on team size, the return of AA games, and what's next Plus: how Kepler plans to be the A24 for games, and why a follow-up to Clair Obscur won't involve a big studio expansion Image credit: Sandfall Interactive Feature by Lewis Packwood Contributor Published on May 27, 2025 The success of Clair Obscur: Expedition 33 – which sold 2 million copies within 12 days of launch – has meant all eyes are now on its developer, Sandfall Interactive. As the games industry mulls how to move forward, faced with a saturated market, widespread layoffs and spiralling development costs, the fact that an original title made by a relatively small team could see such massive success gives hope to everyone. It's also an emphatic validation of the strategy of Clair Obscur's publisher, Kepler Interactive, which since its formation in 2021 has focused on original titles with eye-catching art styles and mould-breaking gameplay, including Sifu, Tchia, Scorn, Pacific Drive, Ultros, Bionic Bay, and the upcoming Rematch. "They respect creativity and innovation in games, they have a very high standard in choosing games to publish, and they are very fun people to work with," enthuses Shuhei Yoshida, former president of Sony Interactive Entertainment Worldwide Studios, and now a freelance consultant for Kepler. Yoshida has been helping to evaluate game pitches for the publisher since he left Sony in January, as well as helping to promote Bionic Bay and Clair Obscur. "They have a great balance in looking for innovation in games and investing in commercially viable projects," he says. "I think the way Kepler chooses games and supports developers is a great example of sustainable indie publishing. I expect many companies in the industry will look for inspiration from what Kepler is doing." Coop mode One thing that immediately marks out Kepler as different is its structure. "Kepler is co-owned by a group of studios, but they all operate autonomously," explains portfolio director Matthew Handrahan, who joined Kepler from PlayStation in 2022 (before that, he was editor-in-chief of this very site). "They make a lot of their own choices creatively and commercially in terms of the direction of their business. But there is a collaborative aspect that they can draw upon if they feel they need it. The thing that we definitely are very clear on is Kepler is not sitting here telling anyone what to do." The idea is that Kepler can provide support into each studio in terms of things like HR, legal teams, and IT. "And each one of them can draw on that to the degree that they want to, in the belief that if you give people that solid base, they can just focus more on being creative," says Handrahan. Image credit: Sandfall Interactive But the plan was always for Kepler to become a third party publisher, he continues. So in addition to publishing games from its own studios, since 2024 Kepler has started releasing games from outside developers, like Pacific Drive, Clair Obscur, and the newly signed PVKK from Bippinbits, the creators of Dome Keeper. "As we go forward, what we really hope is that people can spot a Kepler game," says Handrahan. So what marks out a Kepler title? CEO Alexis Garavaryan has previously emphasised the publisher champions games with "bold art direction and innovative game design" that avoid familiar influences like Star Wars and superheroes. Handrahan says this is essential in today's market. "I remember writing about Steam being overcrowded for GamesIndustry.biz 10 years ago, and saying, 'Oh, there's too many games'," he says. "Well there's five times more games being released now. So if you are coming to market with a game, it had better be doing something genuinely fresh." What Kepler definitely isn't doing is chasing trends, which Handrahan says is a dangerous strategy. He gives the example of Balatro imitators. "If you're making something hot on the heels of that, by the time you get to market, there'll probably be 150 other alternatives." One can't help thinking, too, of the expensive failure of Concord at PlayStation, which proved to be one hero shooter too many. The next expedition Sandfall's COO and producer François Meurisse says that the fact that studio head Guillaume Broche was deliberately avoiding chasing trends with Clair Obscur was what attracted him to join in the first place. "Some people predicted to us that it was a tricky [sector] when we started development, and there could be kind of a curse on AA games" François Meurisse, Sandfall Interactive He was immediately on board with Broche's passion for revitalising the kind of flashy, 3D, turn-based JRPGs that had long gone out of fashion. That passion came first: the strategy came later. "A bit after, when we tried to rationalise that yearning he has for this kind of game, we realised that it wasn't addressed as much in the market, and maybe there was a place for it," says Meurisse. The end result went beyond their wildest dreams. "The game has had success to an extent that we didn't imagine," he says. "We smashed our forecasts pretty fast." Naturally, thoughts are already turning to a follow-up. "There will be another video game, for sure," says Meurisse, adding that it's a little early to say exactly what form it will take. "I can't wait to dig more into the ideas we already have for the next game," he says. "Plus the team has grown up, has acquired new skills throughout production," he says. "Many of them were junior when we started. We learned to work together. So I can't wait to get to the next project, because we'll start from a more efficient position than when we started the company five years ago. And that [comes] with higher expectations as well, so it will be challenging. But I can say that we have – and Guillaume in particular has – great ideas for the next game." AA comeback Image credit: Sandfall Interactive The success of Clair Obscur has led many to herald the comeback of AA games, a sector that has shrunk significantly over the past couple of console generations – even if it's a harder category to define in 2025 based on a lack of publicly available budget numbers. "Some people predicted to us that it was a tricky [sector] when we started development, and there could be kind of a curse on AA games," remembers Meurisse. "But from our perspective, we didn't care too much about market considerations. […] In a sense, A Plague Tale or Mortal Shell or Hellblade, games like those were already proof for us that small teams of less than 50 people could have great games and great execution." Speaking of team size, much was made of the claim that Clair Obscur was created by a team of around 30, although many were quick to point out that the credits include dozens more people than that, working on things like QA, localization and voice production, as well as a ‘gameplay animation' team in Korea. "These kinds of games did exist in much greater numbers about 15 years ago, and I think there are some threads that the AAA industry lost as they grew and grew and grew" Matt Handrahan, Kepler Interactive So was the game mis-sold? "I don't think so," says Handrahan. "I think that the creative engine of the game was that group of 30. […] In terms of what the game is – the vision of it and the way in which it's executed – [that] does come from that nucleus of staff that is at Sandfall." "In terms of main credits over the four years of production, we were on average about 30 people," clarifies Meurisse. "We started with less than 10 people, scaled up until 30, and close to 40, and then scaled a little bit down. You mentioned Korean animators, but it's important to mention that none of them were full time. They were doing some extras beside some other jobs of animation. So the core team was on average 30 people in the home studio, plus privileged contractors like the lead writer or the composer, for example: I include them in that core team." "But of course, we had a galaxy of partners revolving around the project. Kepler in the first place – and I want to really pinpoint that they were really key in the success of the game – plus some other creative people as well, like musician players, translators, QA testers also. And that definitely extends the team, and I'm super grateful we could work with all those super […] passionate partners from all over the world." "I think people fixated on this number," adds Handrahan, "but actually the more useful thing that was being said was that this is not a AAA game, right? You can look at those credits, and it's still definitely not a AAA game." "These kinds of games did exist in much greater numbers about 15 years ago, and I think there are some threads that the AAA industry lost as they grew and grew and grew, and brought in different ways of monetising," he continues. "We have to remember there was a time when AAA companies were making games like Vanquish and Mirror's Edge and Kane & Lynch, and all of these really cool, interesting, not small games, but much smaller scale games. And you've seen the number of releases from AAA publishers dwindle and dwindle and dwindle. Now there's an opportunity for teams like Sandfall to come in and give players something that they really have not been given for quite a long time." Which leads us to ask, if Clair Obscur can't be classed as a AAA game, how much did it cost, exactly? Neither Handrahan nor Meurisse is willing to disclose the true figure. "I would say that I've seen a lot of budget estimations that are all higher than the real budget," muses Meurisse. Handrahan agrees. "Everybody's desperate to know what the budget is, and I won't tell them, but I would guarantee if you got 10 people to guess, I think all 10 wouldn't guess the actual figure," he says. "I'm sure Mirror's Edge and Vanquish cost more, put it that way." Keeping the team small Image credit: Sandfall Interactive With a success like Clair Obscur, the temptation might be to scale up the studio for a blockbuster sequel: a pattern we've seen with successful franchises many times before. But Meurisse says that's something Sandfall wants to avoid. "For now, our vision would be to stick to a close team working in the same city with less than 50 people on board, focusing on one project after another, and keeping this agility, and this creative strength, and smartness of a small group of passionate people wanting to do something big," he says. "That's how video games were made for years," he continues. "The team that made Ocarina of Time or Half-Life 2, I think those were max 60 or 70 people*, and that kind of size allows for good decisions and great creativity." He adds that the studio might recruit a few more members, but it won't start working on multiple projects simultaneously, and they will deliberately avoid growing too big and unwieldy. "We want to keep the organisation that made us successful," he says. Handrahan notes that because game making is an iterative process, maintaining only a small permanent team makes sense. "I think keeping a core team to hold the vision and to build out what the game is, and then expanding as you need to through things like outsourcing, is a very smart and sustainable way to manage game development," he says. "I think that there's been a lot of irresponsible practices in the industry," he continues, referring to the inherent risks involved in ballooning AAA budgets and team sizes. "Some games can make it work. Grand Theft Auto 6 is going to make it work, I think we can all say with great confidence. But there are plenty of games made with very large teams and for huge amounts of money that don't land, and there is a human cost to running things that way. People lose their jobs. God knows how many layoffs there's been in the industry over the last few years." He worries that the temptation to scale up is too great. "I do see a lot of developers who ship a game and then get some level of success – even very small levels of success or on very small budgets – and then almost instinctively feel like they need to double or triple the budget of the next game. And that is something I definitely question." No bloat He also questions the need to make games bigger. "One of the things that's great about Expedition 33 is it really respects the player's time. It gives them plenty to do, and it gives them plenty of satisfaction, but it isn't arbitrarily 500 hours of gameplay. It's impactful because it's scoped correctly. […] It doesn't have any sense of bloat or extraneous things that are put there just to make it larger and larger and larger." "Brevity should be more of a virtue in gaming," he adds. "Something can be better by being shorter – something that's being discussed in film at the moment. Every film seems to be two and a half hours long, and I think most people are like, 'Can they all be a bit shorter, please? Because we have other things to do with our lives'." Meurisse notes that the focus for Clair Obscur was always on quality over quantity. "From the beginning, we wanted to do an intense and short experience," he says. "The first length estimates of the game were closer to 20 hours for the main quest. I think we ended up closer to 30, even 40 hours if you take a bit of time. As a player, there are so many great games out there that I want to experience, [and] what's important to me is the level of excitement and fun I get from a game, rather than how long it is." He also questions the link between game length and price. "The value that players get from games does not align systematically with the length of the game," he says. "For example, one of my favourite games of all time is Inside, which lasts about two hours, but it's one of the most polished, and intense [experiences] – and even life changing for some people." What are games worth? Notably, Clair Obscur launched at a price point of $50/$45, at a time when the standard price for big-budget games is creeping up to $80. "I think as that AAA price goes up, I think it creates more of an opportunity to be launching games – more sensibly scoped games – [and] pricing them at that $40–50 range," says Handrahan. "And I don't think anyone that played Expedition 33 would think they didn't get their money's worth out of that." "When we announced the pricing at $50 we did actually have a little of a backlash online," adds Meurisse, "with people fearing it would be a 12-hour-long game with unfinished content, and that it was suspicious to have a $50 game that was looking like this in the trailers. But in the end we stuck with the price, we doubled down on it, [and] we provided some context about the fact that it wasn't a AAA." "In the end, it was a win-win situation, because it was a way to attract more players towards the game, to have good player satisfaction about their buying [decision], and it could actually end up doing more sales. So maybe players' perception can change a bit about that kind of price [point]." The Kepler brand Image credit: Sandfall Interactive Clair Obscur has obviously provided a huge boost for Kepler as a publisher, and Handrahan says the plan now is for Kepler to build a brand as the home for high-quality, mid-sized games with a unique vision. He gives the newly signed PVKK as an example. "The art direction is very high quality, it's very, very bold. It has a strong narrative component. It has innovative gameplay design. It speaks to wider culture, it's not an insular vision for a game. I think you get a lot of games that are kind of just about other games, and that is not something we're interested in necessarily." It's a model that he thinks others could follow. "We definitely want there to be strong associations with the games we do, so if that is something that other publishers could imitate or follow along from, then all the better," he says, adding that it makes little sense for publishers to cast a broad net of styles and genres in such a crowded market. But of course, there is a risk to championing unique, untested visions. So what does Kepler do to mitigate that risk? "We definitely do market research," says Handrahan – although he adds that ultimately the process is subjective. "I came to this company because I really trusted the taste of the people that I work for. I have always felt that if I'm really excited by a game, there will be other people out there who are excited by it. Yes, you can test that against market research, and that is definitely a function that we have in the company, and we use it. But our litmus test is a subjective level of excitement and belief in the vision and creativity that we see in the games that we sign." He points to companies in other media, like A24 or Warped Records, that have taken a similar approach with great success. "We want to be that in games." *Fact check note: Valve's core team was actually 84 for Half-Life 2, without including the many people involved in voice acting, QA, IT, legal, and so on. The team behind Legend of Zelda: Ocarina of Time numbered around 66, although the people involved in QA testing aren't listed individually in the credits.

Villa Il Bel Canto / CLAB ArchitetturaSave this picture!© Andrea CerianiHouses, Refurbishment•Cavaion Veronese, Italy Architects: CLAB Architettura Area Area of this architecture project Area:  500 m² Year Completion year of this architecture project Year:  2024 Photographs Photographs:Andrea Ceriani Manufacturers Brands with products used in this architecture project Manufacturers:  Gessi, Louis Poulsen, Artemide, Azzurra ceramica, FLOS, Fritz Hanesen, Legrand / Bticino, NIC design, RABATTO, Tip Top Fenster Lead Architects: Matteo Fiorini, Giulia Salandini, Andrea Castellani More SpecsLess Specs Save this picture! "Il Bel Canto" is a rural estate comprising multiple buildings, with its main nucleus established in the landscape of Cavaion Veronese since the mid-18th century. In addition to the main house, the property features a small wine production from the surrounding vineyards, as well as olive groves and a small woodland that define the landscape.Save this picture!Save this picture!Save this picture!Save this picture!The architectural intervention focused on the renovation of the interior spaces of the main family home, drawing inspiration from the existing elements such as arches, porches, and courtyard spaces, while establishing a dialogue with some of the house's original materials. Two newly designed elements, positioned on the ground floor and the top floor, reshape the interiors, creating new perspectives and connections between spaces. In addition to enhancing the family's collection of prints, paintings, artworks, and design pieces, these elements integrate functional features, transforming into a bookshelf, bar area, pantry, and wardrobe.Save this picture!Save this picture!Save this picture!The selected materials and colors, including oak wood and a deep red hue, harmonize with the existing flooring and the surrounding landscape. A light resin flooring defines and connects the renovated areas, while copper cladding characterizes the central kitchen island, around which the functional space is organized. The existing marble fireplaces further enhance the convivial character of the house, which opens to the outdoors, embracing the natural seasonal rhythm typical of a countryside home.Save this picture! Project gallerySee allShow less About this officeCLAB ArchitetturaOffice••• MaterialStoneMaterials and TagsPublished on May 25, 2025Cite: "Villa Il Bel Canto / CLAB Architettura" 25 May 2025. ArchDaily. Accessed . <https://www.archdaily.com/1030450/villa-il-bel-canto-clab-architettura&gt ISSN 0719-8884Save世界上最受欢迎的建筑网站现已推出你的母语版本!想浏览ArchDaily中国吗?是否 You've started following your first account!Did you know?You'll now receive updates based on what you follow! Personalize your stream and start following your favorite authors, offices and users.Go to my stream

Casa SA207 | © Diego Vázquez Mellado Casa SA207 by Vázquez Mellado is situated in the historic city of Querétaro, Mexico, on a narrow site measuring 8.70 meters in width and extending 37 meters in depth. The lot’s proportions posed a particular challenge, which the architects addressed by drawing inspiration from the traditional courtyard houses in Querétaro’s historic center. In these historic residences, the courtyard, or patio, serves as a passive climate moderator and a spatial and social nucleus. Casa SA207 revisits this typology through a contemporary lens, offering a nuanced response to privacy, density, and domesticity in the urban fabric. Casa SA207 Technical Information Architects1-3: Vázquez Mellado Location: Querétaro, Mexico Area: 362.47 m2 | 3,900 Sq. Ft. Completion Year: 2025 Photographs: © Diego Vázquez Mellado The patio is not just a spatial element but the heart of the home. It welcomes, shelters, and connects, offering a sense of peace and belonging within the density of the city. – Diego Vázquez Mellado Casa SA207 Photographs © Diego Vázquez Mellado © Diego Vázquez Mellado © Diego Vázquez Mellado © Diego Vázquez Mellado © Diego Vázquez Mellado © Diego Vázquez Mellado © Diego Vázquez Mellado © Diego Vázquez Mellado © Diego Vázquez Mellado © Diego Vázquez Mellado © Diego Vázquez Mellado Spatial Organization and Domestic Hierarchies The project’s street-facing façade is entirely closed off, with no visible windows or apertures. This gesture reinforces privacy and anonymity within the city while turning the house inward. At the rear of the property, the architects introduced a direct connection to a neighboring public park, anchoring the residence within both private and communal realms. The courtyard, centrally within the linear plan, acts as a fulcrum that mediates light, views, and circulation. It is both the spatial heart and the conceptual axis of the home. The house is organized into a two-level scheme, with the ground floor dedicated to shared family life and the upper floor reserved for private functions. The spatial strategy intentionally encourages daily activity and interaction on the ground level. The living and dining rooms are placed at the far end of the house, adjacent to the public park. These areas are balanced by a kitchen and TV room positioned toward the front of the lot. Both rooms are oriented toward the central courtyard, promoting visual connectivity and natural ventilation. On the upper level, bedrooms and a modest study are distributed linearly. These spaces are compact by design, reinforcing their function as retreats for rest and contemplation rather than prolonged daytime activity. The reduced footprint of the upper floor emphasizes the hierarchy of domestic life envisioned by the architects: a house where familial engagement and collective routines unfold at ground level and where privacy is quiet and unobtrusive. The courtyard acts as the project’s spatial and psychological anchor. Its tall enclosing walls and dense vegetation cultivate a sense of introspection, calm, and disconnection from the surrounding city. It is not merely a source of daylight or ventilation but a place of stillness, where time slows, and attention turns inward. Materiality and Constructive Logic The project is defined materially by the use of clay brick, chosen for its durability, thermal properties, and ability to age gracefully over time. This decision reflects a clear commitment to low-maintenance living and constructive honesty. The brick’s modularity also provides flexibility for future adaptations without disrupting the architectural language of the house. One of the project’s defining features is the 6-meter-high wall that borders the courtyard. This vertical surface acts as a visual barrier while allowing the interior spaces to remain open to the patio without compromising privacy. The wall also contributes to a sense of enclosure and sanctuary within the house, allowing residents to draw their curtains or leave them open without concern for external views. Throughout the project, the material palette is restrained, composed primarily of exposed brick, wood, and concrete. This simplicity reinforces the architectural clarity of the design and allows spatial relationships to take precedence over decorative elements. The detailing is modest and measured, aligning with the overall ethos of the project. Reflections on Typology and Contemporary Living Casa SA207 thoughtfully explores the courtyard as an enduring architectural typology. By foregrounding the patio not just as a design feature but as the organizing principle of the entire house, the architects offer a model for contemporary living that prioritizes inwardness, serenity, and slow rhythms. The house precisely negotiates the tension between urban density and domestic refuge, creating a spatial narrative grounded in tradition and responsive to present-day needs. The project demonstrates how compact urban living does not necessitate compromise in spatial quality. Through careful program, form, and material orchestration, Casa SA207 invites reconsidering how architecture can shape the conditions for a more deliberate and connected way of living. In its restraint, the house resists spectacle and offers a quiet, rigorous architecture rooted in site, culture, and human experience. Casa SA207 Plans Ground Level | © Vázquez Mellado Upper Level | © Vázquez Mellado Roof Level | © Vázquez Mellado Section | © Vázquez Mellado Elevation | © Vázquez Mellado Casa SA207 Image Gallery About Vázquez Mellado Vázquez Mellado is a Mexican architectural design studio based in Querétaro. They are known for their thoughtful reinterpretation of traditional typologies through contemporary forms and materials. Led by Jorge and Diego Vázquez Mellado, the firm explores spatial intimacy, privacy, and material honesty across residential and cultural projects. Credits and Additional Notes Lead Architects: Jorge Vázquez Mellado, Diego Vázquez Mellado Collaborators: Elvia Torres, Adelfo Pérez, Norma Velázco, Jorge Uribe Landscape Design: Matorral Estudio

Sheppard Robson received an award for its four-storey Nucleus Building at the University of Edinburgh, while Architype also won for a very different education scheme: its 550-place Riverside Primary School in Perth.  Three further winning projects are in Scottish cities, including Collective Architecture’s 130-home Ellengowan Regeneration scheme in Dundee and Stallan Brand Architecture + Design and LDA Design’s £28 million overhaul of Aberdeen’s Union Terrace Gardens.  The other urban project is Holmes Miller Architects’s £85 million HMP and YOI for women prisoners in Stirling, while MLA was recognised for its Rosebank Distillery refurbishment scheme in Falkirk, on the bank of the Forth and Clyde Canal. Advertisement Three Highland projects were given RIAS Awards, including two castle restoration projects near Inverness: Ptolemy Dean Architects’ Aldourie Caste Estate and Simpson & Brown’s Fairburn Tower.  GRAS was given an award for its overhaul of Kinloch Lodge, a Victorian sporting lodge in Sutherland, while Izat Arundell received an award for the only non-mainland scheme: Caochan na Creige, a stone home on the Isle of Harris.  Source:Richard GastonCaochan na Creige, Isle of Harris by Izat Arundell The list of winners is rounded off by an infrastructure scheme: Moxon Architects’ Gairnshiel Jubilee Bridge in Aberdeenshire.  The 11 victorious schemes now become the ‘longlist’ for the RIAS Andrew Doolan Best Building in Scotland Award. The shortlist for that prize will be announced in July ahead of the winner announcement in November. RIAS had originally shortlisted 21 projects for its awards. Schemes by Hassel, Fraser/Livingstone, Ryder Architecture, Threesixty Architecture, Loader Monteith and Reiach and Hall are among those to miss out.Advertisement The successful RIAS Award winners will be considered for the RIBA National Awards, which will also be made public in July. The jury for the 2025 RIAS Awards was chaired by Jessam Al-Jawad, director of Al-Jawad Pike, who visited the projects alongside fellow judges Caroline Grewar, programme director at V&A Dundee, Craig Hamilton of Craig Hamilton Architects and Ann Nisbet of Ann Nisbet Studio.  Al-Jawad said: ‘This year’s RIAS Awards winners show an inspiring range of responses to Scotland’s landscapes, communities, and heritage – from quietly transformative conservation to bold public architecture. ‘Across the board, we saw a deep care for context, sustainability and the people who use these buildings. Taken together, these projects demonstrate the extraordinary breadth of talent in Scottish architecture today.’  Source:Simpson & BrownFairburn Tower, Highlands by Simpson & Brown The 2025 RIAS Awards winners Aldourie Castle Estate, Highlands by Ptolemy Dean Architects Caochan na Creige, Isle of Harris by Izat Arundell Ellengowan Regeneration, Dundee by Collective Architecture Fairburn Tower, Highlands by Simpson & Brown Gairnshiel Jubilee Bridge, Aberdeenshire by Moxon Architects HMP & YOI Stirling by Holmes Miller Architects Kinloch Lodge, Highland by GRAS Riverside Primary School, Perth by Architype Rosebank Distillery, Falkirk by MLA The Nucleus Building, University of Edinburgh by Sheppard Robson Union Terrace Gardens, Aberdeen by Stallan-Brand Architecture + Design & LDA Design Nucleus. University of Edinburgh King's Buildings Campus.

May 20, 2025Could Mitochondria Be Rewriting the Rules of Biology?New discoveries about mitochondria could reshape how we understand the body’s response to stress, aging, and illness. Scientific AmericanSUBSCRIBE TO Science QuicklyRachel Feltman: Mitochondria are the powerhouse of the cell, right? Well, it turns out they might be way more complicated than that, and that could have implications for everything from diet and exercise to treating mental health conditions.For Scientific American’s Science Quickly, I’m Rachel Feltman.Our guest today is Martin Picard, an associate professor of behavioral medicine at Columbia University. He’s here to tell us all about our mitochondria, what they do for us and how they can even talk to each other. If you like to watch your pods instead of just listening, you can check out a video version of my conversation with Martin over on our YouTube page. Plus, you’ll get to see some of the aligning mitochondria we’re about to talk about in action.On supporting science journalismIf you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.Martin, would you tell us a little bit about who you are and where you work?Martin Picard: Sure, I work at Columbia University; I’m a professor there, and I lead a team of mitochondrial psychobiologists, so we try to understand the, the mind-mitochondria connection, how energy and those little living creatures that populate our cells, how they actually feed our lives and allow us to, to be and to think and to feel and to experience life.Feltman: Before we get into the details, most people know mitochondria as the “powerhouse of the cell”—which, fun fact, Scientific American actually coined in the 1950s—but what are mitochondria, to start us off with a really basic question?Picard: [Laughs]Yes, 1957 is the “powerhouse of the cell.” That was momentous.That shaped generations of scientists, and now the powerhouse analogy is expired, so it’s time for a new perspective.Really, mitochondria are, are small living organelles, like little organs of the cell, and what they do is they transform the food we eat and the oxygen that we breathe. Those two things converge inside the mitochondria, and that gets transformed into a different kind of energy. Energy is neither created nor destroyed, right? It’s a fundamental law of thermodynamics. So mitochondria, they don’t make energy; they transform the energy that’s stored in food from the plants and from the energy of the sun and then the oxygen combining this, and then they transform this into a little electrical charge. They dematerialize food—energy stored in food—into this very malleable, flexible form of energy that’s membrane potential, so they become charged like little batteries and then they power everything in our cells, from turning on genes and making proteins and cellular movement; cellular division; cell death, aging, development—everything requires energy. Nothing in biology is free.Feltman: Well, I definitely wanna get into what you said about the powerhouse analogy not working anymore ’cause that seems pretty huge, but before we get into that: you recently wrote a piece for Scientific American, and you referred to yourself as, I think, a “mitochondriac.” I would love to hear what you mean by that and how you got so interested in these organelles.Picard: Yeah, there’s a famous saying in science: “Every model is wrong, but some are useful.” And the model that has pervaded the world of biology and the health sciences is the gene-based model (the central dogma of biology, as it’s technically called): genes are the blueprint for life, and then they drive and determine things. And we know now [it] to be misleading, and it forces us to think that a lot of what we experience, a lot of, you know, health or diseases, is actually determined by our genes. The reality is a very small percentage [is].Whether we get sick or not and when we get sick is not driven by our genes, but it’s driven by, you know, emergent processes that interact from our movement and our interaction with other people, with the world around us, with what we eat, how much we sleep, how we feel, the things we do. So the gene-based model was very powerful and useful initially, and then, I think, its, its utility is dwindling down.So the powerhouse analogy powered, you know, a few [laughs] decades of science, and then what started to happen, as scientists discovered all of these other things that mitochondria do, we kept getting surprised. Surprise is an experience, and when you feel surprised about something, like, it’s because your internal model of what that thing is, it was wrong, right?Feltman: Right.Picard: And when there’s a disconnect between your internal model and the, the reality, then that feels like surprise. And I grew up over the last 15 years as a academic scientist, and, like, every month there’s a paper that’s published: “Mitochondria do this. Mitochondria make hormones.” Surprise! A, a powerhouse should have one function: it should make, or transform, energy, right? This is what powerhouses do. Mitochondria, it turns out, they have a life cycle. They make hormones. They do transform energy, but they also produce all sorts of signals. They turn on genes; they turn off genes. They can kill the cell if they deem that’s the right thing to do.So there are all of these functions, and, and I think, as a community, we keep being surprised as we discover new things that mitochondria do. And then once you realize the complexity and the amazing beauty of mitochondria and their true nature, then I think you have to become a mitochondriac [laughs]. You have to, I think, be impressed by the beauty of—this is just a—such a beautiful manifestation of life. I fell in love with mitochondria, I think, is what happened [laughs].Feltman: Yeah, well, you touched on, you know, a few of the surprising things that mitochondria are capable of, but could you walk us through some of your research? What surprises have you encountered about these organelles?Picard: One of the first things that I saw that actually changed my life was seeing the first physical evidence that mitochondria share information ...Feltman: Mm.Picard: With one another. The textbook picture and the powerhouse analogy suggests that mitochondria are these, like, little beans and that they, they kind of float around and they just make ATP, adenosine triphosphate, which is the cellular energy currency, and once in a while they reproduce: there’s more mitochondria that come from—mitochondria, they can grow and then divide. So that’s what the powerhouse predicts.And what we found was that when—if you have a mitochondrion here and another mitochondrion here, inside the mitochondria, they’re these membranes ...Feltman: Mm.Picard: They’re, like, little lines. They look, in healthy mitochondria, look like radiators, right? It’s, like, parallel arrays. And it’s in these lines that the oxygen that we breathe is consumed and that the little charge—the, the food that we eat is converted into this electrical charge. These are called cristae.And in a normal, healthy mitochondria the cristae are nicely parallel, and there’s, like, a regularity there that’s just, I think, intuitively appealing, and it, it looks healthy. And then if you look at mitochondria in a diseased organ or in a diseased cell, often the cristae are all disorganized. That’s a feature of “something’s wrong,” right?And I’ve seen thousands of pictures and I’ve taken, you know, several thousands of pictures on the electron microscope, where you can see those cristae very well, and I’d never seen in the textbooks or in articles or in presentations, anywhere, that the cristae could actually, in one mitochondrion, could be influenced by the cristae in another mitochondrion.And what I saw that day and that I explained in the [laughs], in the article was that there was this one mitochondrion there—it had beautifully organized cristae here, and here the cristae were all disorganized. And it turns out that the part of this mitochondrion that had beautifully organized cristae is all where that mitochondria was touching other mitochondria.Feltman: Mm.Picard: So there was something about the mito-mito contact, right? Like, a unit touching another unit, an individual interacting with another individual, and they were influencing each other ...Feltman: Yeah.Picard: And the cristae of one mitochondrion were bending out of shape. That’s not thermodynamically favorable [laughs], to bend the lipid membrane, so there has to be something that is, you know, bringing energy into the system to bend the membrane, and then they were meeting to be parallel with the cristae of another mitochondrion. So there was these arrays that crossed boundaries between individual mitochondria ...Feltman: Wow.Picard: And this was not [laughs] what I, I learned or this was not what I was taught or that I’d read, so this was very surprising.The first time we saw this, we had this beautiful video in three dimension, and I was with my colleague Meagan McManus, and then she realized that the cristae were actually aligning, and we did some statistics, and it became very clear: mitochondria care about mitochondria around them ...Feltman: Yeah.Picard: And this was the first physical evidence that there was this kind of information exchange.When you look at this it just looks like iron filings around a magnet.Feltman: Mm.Picard: Sprinkle iron filings on the piece of paper and there’s a magnet underneath, you see the fields of force, right? And fields are things that we can’t see, but you can only see or understand or even measure the strength of a field by the effect it has on something. So that’s why we sprinkle iron filings in a magnetic field to be able to see the field.Feltman: Right.Picard: It felt like what we were seeing there was the fingerprint of maybe an underlying electromagnetic field, which there’s been a lot of discussion about and hypothesis and some measurements in the 1960s, but that’s not something that most biologists think is possible. This was showing me: “Maybe the powerhouse thing is, is, is, is not the way to go.”Feltman: Did you face any pushback or just general surprise from your colleagues?Picard: About the cristae alignment?Feltman: Yeah.Picard: I did a lot of work. I took a lot of pictures and did a lot of analysis to make sure this was real ...Feltman: Mm.Picard: So I think when I presented the evidence, it was, it was, you know, it was clear [laughs].Feltman: Right.Picard: This was real.Feltman: Yeah.Picard: Whether this is electromagnetic—and I think that’s where people have kind of a gut reaction: “That can’t be real. That can’t be true.”Feltman: Mm.Picard: The cristae alignment is real, no questioning this, but whether this—there’s a magnetic field underlying this, we don’t have evidence for that ...Feltman: Sure.Picard: It’s speculation, but I think it, it hits some people, especially the strongly academically trained people that have been a little indoctrinated—I think that tends to happen in science ...Feltman: Sure.Picard: I think if we wrote a grant, you know, to, to [National Institutes of Health] to study the magnetic properties of mitochondria, that’d be much harder to get funded. But there was no resistance in accepting the visual evidence of mitochondria exchanging information ...Feltman: Yeah.Picard: What it means, then, I think, is more work to be done to—towards that.Feltman: If, if we were seeing an electromagnetic field, what would the implications of that be?Picard: I think the implications is that the model that most of biomedical sciences is based on, which is “we’re a molecular soup and we’re molecular machines,” that might not be entirely how things work. And if we think that everything in biology is driven by a lock-and-key mechanism, right—there’s a molecule that binds a receptor and then this triggers a conformational change, and then there’s phosphorylation event and then signaling cascade—we’ve made a beautiful model of this, a molecular model of how life works.And there’s a beautiful book that came out, I think last year or end of 2023, How Life Works, by Philip Ball, and he basically brings us through a really good argument that life does not work by genetic determinism, which is how most people think and most biologists think that life works, and instead he kind of brings us towards a much more complete and integrative model of how life works. And in that alternate model it’s about patterns of information and information is carried and is transferred not just with molecules but with fields. And we use fields and we use light and we use, you know, all sorts of other means of communication with technology; a lot of information can be carried through your Bluetooth waves ...Feltman: Mm.Picard: Right? Fields. Or through light—we use fiber optic to transfer a lot of information very quickly. And it seems like biology has evolved to, to harness these other ways of, of nonmolecular mechanisms of cell-cell communication or organism-level communication.There’s an emerging field of quantum biology that is very interested in this, but this clashes a little bit with the molecular-deterministic model that science has been holding on to [laughs]—I think against evidence, in, in some cases—for a while. Nobody can propose a rational, plausible molecular mechanism to explain what would organize cristae like this across mitochondria. The only plausible mechanism seems to be that there’s a—there’s some field, some organizing electromagnetic field that would bend the cristae and organize them, you know, across organelles, if that’s true.Feltman: Right.Picard: It was a bit of an awakening for me, and it turned me into a mitochondriac because it made me realize that this is the—this whole thing, this whole biology, is about information exchange and mitochondria don’t seem to exist as little units like powerhouses; they exist as a collective.Feltman: Yeah.Picard: The same way that you—this body. It’s a bunch of cells; either you think it’s a molecular machine or you think it’s an energetic process, right? There’s energy flowing through, and are you more the molecules of your body or are you more the, the energy flowing through your body?Feltman: Mm.Picard: And if you go down this, this line of questioning, I think, very quickly you realize that the flow of energy running through the physical structure of your body is more fundamental. You are more fundamentally an energetic process ...Feltman: Hmm.Picard: Than the physical molecular structure that you also are. If you lose part of your anatomy, part of your structure, right—you can lose a limb and other, you know, parts of your, of your physical structure—you still are you ...Feltman: Right.Picard: Right? If your energy flows differently or if you change the amount of energy that flows through you, you change radically. Three hours past your bedtime you’re not the best version of your, the best version of yourself. When you’re hangry, you haven’t eaten, and you, like, also, you’re not the best version of yourself, this is an energetic change. Right?Feltman: Yeah.Picard: Many people now who have experienced severe mental illness, like schizophrenia and bipolar disease, and, and who are now treating their symptoms and finding full recovery, in some cases, from changing their diets.Feltman: Mm.Picard: And the type of energy that flows through their mitochondria, I think, opens an energetic paradigm for understanding health, understanding disease and everything from development to how we age to this whole arc of life that parallels what we see in nature.Feltman: Yeah, so if we, you know, look at this social relationship between mitochondria, what are, in your mind, the most, like, direct, obvious implications for our health and ...Picard: Mm-hmm.Feltman: And well-being?Picard: Yeah, so we can think of the physical body as a social collective. So every cell in your body—every cell in your finger, in your brain, in your liver, in your heart—lives in some kind of a social contract with every other cell. No one cell knows who you are, or cares [laughs], but every cell together, right, makes up who you are, right? And then together they allow you to feel and to have the experience of who you are. That kind of understanding makes it clear that the key to health is really the coherence between every cell.Feltman: Mm.Picard: If you have a few cells here in your body that start to do their own thing and they kind of break the social contract, that’s what we call cancer. So you have cells that stop receiving information from the rest of the body, and then they kind of go rogue, they go on their own. Their purpose in life, instead of sustaining the organism, keeping the whole system in coherence, now these cells have as their mind, like, maybe quite literally, is, “Let’s divide, and let’s make more of ourselves,” which is exactly what life used to be before mitochondria came in ...Feltman: Mm.Picard: Into the picture 1.5 billion years ago, or before endosymbiosis, the origin of, of multicellular life. So cancer, in a way, is cells that have broken the social contract, right, exited this social collective, and then to go fulfill their own little, mini purpose, which is not about sustaining the organism but sustaining themselves. So that principle, I think, has lots of evidence to, to support it.And then the same thing, we think, happens at the level of mitochondria, right? So the molecular-machine perspective is that mitochondria are little powerhouses and they’re kind of slaves to the cell: if the cell says, “I need more energy,” then the mitochondria provide and they kind of obey rules. The mito-centric perspective [laughs] is that mitochondria really drive the show. And because they’re in charge of how energy flows, they have a veto on whether the cell gets energy and lives and divides and differentiates and does all sorts of beautiful things or whether the cell dies.And most people will know apoptosis, programmed cell death, which is a normal thing that happens. The main path to apoptosis in, in our bodies is mitochondria calling the shot, so mitochondria have a veto, and they can decide, “Now, cell, it’s time to die.” And mitochondria make those decisions not based on, like, their own little powerhouse [laughs] perception of the world; they make these decisions as social collectives. And you have the hundreds, thousands of mitochondria in some cells that all talk to each other and they integrate dozens of signals—hormones and metabolites and energy levels and temperature—and they integrate all this information; they basically act like a mini brain ...Feltman: Hmm.Picard: Inside every cell. And then once they have a, a—an appropriate picture of what the state of the organism is and what their place in this whole thing is, then they actually, I think, make decisions about, “Okay, it’s time to divide,” right? And then they send signals to, to the nucleus, and then there’re genes in the nucleus that are necessary for cell division that gets turned on, and then the cell enters cell cycle, and we and others have shown in, in, in the lab, you can prevent a cell from staying alive [laughs] but also from differentiating—a stem cell turning into a neuron, for example, this is a major life transition for a cell. And people have asked what drives those kind of life transitions, cellular life transitions, and it’s clear mitochondria are one of the main drivers of this ...Feltman: Hmm.Picard: And if mitochondria don’t provide the right signals, the stem cell is never gonna differentiate into a specific cell type. If mitochondria exists as a social collective, then what it means for health [laughs] is that what we might wanna do is to promote sociality, right, to promote crosstalk between different parts of our bodies.Feltman: Hmm.Picard: And I suspect this is why exercise is so good for us.Feltman: Yeah, that was—that’s a great segue to my next question, which is: How do you think we can foster that sociality?Picard: Yeah. When times are hard, right, then people tend to come together to solve challenges. Exercise is a, a big challenge for the organism, right?Feltman: Mm.Picard: You’re pushing the body, you’re, like, contracting muscles, and you’re moving or, you know, whatever kind of exercise you’re doing—this costs a lot of energy, and it’s a big, demanding challenge for the whole body. So as a result you have the whole body that needs to come together to survive this moment [laughs]. And if you’re crazy enough to run a marathon, to push your body for three, four hours, this is, like, a massive challenge.Feltman: Sure.Picard: The body can only sustain that challenge by coming together and working really coherently as a unit, and that involves having every cell in the body, every mitochondria in the body talking to each other. And it’s by this coherence and this kind of communication that you create efficiency, and the efficiency is such a central concept and principle in all of biology. It’s very clear there, there have been strong evolutionary forces that have pushed biology to be evolved towards greater and greater efficiency.The energy that animals and organisms have access to is finite, right? There’s always a limited amount of food out there in the world. If there’s food and there are other people with you, your social group, do you need to share this? So if biology had evolved to just eat as much food as possible, we would’ve gone extinct or we wouldn’t have evolved the way we have. So it’s clear that at the cellular level, at the whole organism level, in insects to very large mammals, there’s been a drive towards efficiency.You can achieve efficiency in a few ways. One of them is division of labor. Some cells become really good at doing one thing, and that’s what they do. Like muscles, they contract [laughs]; they don’t, you know, release hormones—or they release some hormones but not like the liver, right?Feltman: Sure.Picard: And the liver feeds the rest of the body, and the liver is really good at this. But the liver’s not good at integrating sensory inputs like the brain. The brain is really good at integrating sensory inputs and kind of managing the rest of the body, but the brain is useless at digesting food or, you know, feeding the rest of the body. So every organ specializes, and this is the reason we’re so amazing [laughs]. This is the reason complex multicellular animals that, you know, that, that have bodies with organs can do so many amazing things: because this whole system has harnessed this principle of division of labor. So you have a heart that pushes blood, and you have lungs that take in oxygen, and that’s the main point: [it’s] the cooperation and the teamwork, the sociality between cells and mitochondria and, and organs that really make the whole system thrive.So exercise does that.Feltman: Yeah.Picard: It forces every cell in the body to work together. Otherwise you’re just not gonna survive. And then there are other things that happen with exercise. The body is a predictive instrument, right ...Feltman: Mm.Picard: That tries to make predictions about what’s gonna happen in the future, and then you adapt to this. So when you exercise and you start to breathe harder the reason you breathe harder, the reason, you know, you need to bring in more oxygen in your body, is because your mitochondria are consuming the oxygen. And when that happens every cell has the ability to feel their energetic state, and when they feel like they’re running out of energy, like if you’re exercising hard and your muscles are burning, your body says, “Next time this happens I’ll be ready.” [Laughs] And it gets ready—it mobilizes this program, this preparatory program, which, which we call exercise adaptation, right—by making more mitochondria. So the body can actually make more mitochondria after exercise.So while you’re exercising, the mitochondria, they’re transforming food and oxygen very quickly, making ATP, and then cells—organs are talking to one another; then you’re forcing this great social collective. Then when you go and you rest and you go to sleep, you lose consciousness [laughs], and then the natural healing forces of the body can work. Now the body says, “Next time this happens I’ll be ready,” and then it makes more mitochondria. So we know, for example, in your muscles you can double the amount of mitochondria you have ...Feltman: Wow.Picard: With exercise training. So if you go from being completely sedentary to being an elite runner, you will about double the amount of mitochondria in, in your muscle. And ...Feltman: That’s really cool.Picard: Yeah. And this seems to happen in other parts of the body as well, including the brain.Feltman: I know that your lab does some work on mitochondria and mental health as well. Could you tell us a little bit more about that?Picard: The ability to mitochondria to flow energy supports basic cellular functions, but it also powers the brain [laughs] and powers the mind, and our best understanding now of what is the mind—and consciousness researchers have been debating this for a long time—I think our, our best, most parsimonious definition of the mind is that the mind is an energy pattern. And if the flow of energy changes, then your experience also changes. And there’s emerging evidence in a field called metabolic psychiatry that mental health disorders are actually metabolic disorders ...Feltman: Hmm.Picard: Of the brain.There’s several clinical trials—some are published, many more underway—and the evidence is very encouraging that feeding mitochondria a certain type of fuel, called ketone bodies, brings coherence into the organism. And energetically we think this reduces the resistance to energy flow so energy can flow more freely through the neurons and through the structures of the brain and then through the mitochondria.And that—that’s what people report when they, they go into this medical ketogenic therapy: they feel like they have more energy, sometimes quite early, like, after a few days, sometimes after a few weeks. And then the symptoms of, of mental illness in many people get better. The website Metabolic Mind has resources for clinicians, for patients and, and guidance as to how to—for people to work with their care team, not do this on their own but do this with their medical team.Feltman: And I know that mitochondria have kind of a weird, fascinating evolutionary backstory.Picard: They used to be bacteria, and once upon a time, about two billion years ago, the only thing that existed on the planet that was alive were unicellular, right, single-cell, bacteria, a single-cell organism. And then some bacteria—there were different kinds—and then some bacteria were able to use oxygen for energy transformation; that was—those are called aerobic, for oxygen-consuming. And then there are also anaerobic, non-oxygen-consuming, bacteria that are fermenting cells.And then at some point, about 1.5 billion years ago, what happened is there was a small aerobic bacterium, an alphaproteobacterium, that either infiltrated a larger anaerobic cell or it was the larger cell that ate the small aerobic bacterium, the large one kept it in, and then the small aerobic bacterium ended up dividing and then became mitochondria. So mitochondria used to be this little bacterium that now is very much part of what we are, and what seems to have happened when this critical kind of merger happened is that a new branch of life became possible.Feltman: Yeah.Picard: And animals became possible. And somehow this acquisition, from the perspective of the larger cell, enabled cell-cell communication, a form of cell-cell communication that was not possible before. And this seems to have been the trigger for multicellular life and the development of, initially, little worms and then fishes and then animals and then eventually Homo sapiens.Feltman: Yeah, and that was really controversial when it was first proposed, right?Picard: Yeah. Lynn Margulis, who is, like, a fantastic scientist, she proposed this, and I think her paper was rejected [15] times ...Feltman: Wow.Picard: Probably by Nature and then by a bunch of [laughs] ...Feltman: [Laughs] Sure.Picard: A bunch of other journals. Fourteen rejections and then in the end she published it, and now this is a cornerstone of biology. So kudos for persistence ...Feltman: Yeah.Picard: For Lynn Margulis.Feltman: And mitochondria have just been shaking things up for, for decades [laughs], I guess.Picard: Mm-hmm, yeah, there’ve been several Nobel Prizes for understanding how mitochondria work—specifically for the powerhouse function of mitochondria [laughs].The field of [molecular] mitochondrial medicine was born in the ’80s. Doug Wallace, who was my mentor as a postdoc, discovered that we get our mitochondria from our mothers. The motherly nourishing energy [laughs] is passed down through mitochondria. There’s something beautiful about that.Feltman: Yeah. Thank you so much for coming in. This was super interesting, and I’m really excited to see your work in the next few years.Picard: Thank you. My pleasure.Feltman: That’s all for today’s episode. Head over to our YouTube page if you want to check out a video version of today’s conversation. We’ll be back on Friday with one of our deep-dive Fascinations. This one asks whether we can use artificial intelligence to talk to dolphins. Yes, really.While you’re here, don’t forget to fill out our listener survey. You can find it at sciencequickly.com/survey. If you submit your answers in the next few days, you’ll be entered to win some free Scientific American swag. More importantly, you’ll really be doing me a solid.Science Quickly is produced by me, Rachel Feltman, along with Fonda Mwangi, Kelso Harper, Naeem Amarsy and Jeff DelViscio. This episode was edited by Alex Sugiura. Shayna Posses and Aaron Shattuck fact-check our show. Our theme music was composed by Dominic Smith. Subscribe to Scientific American for more up-to-date and in-depth science news.For Scientific American, this is Rachel Feltman. See you next time!