Mark A Smith @mark_smith89

VP debates are often of little note. This one will be different because Trump is close to 80, a bit addled and still riddled by legal problems. So there is a more than trivial chance that if Trump is elected, @JDVance will become POTUS. Americans should watch with that in mind.

This morning, Nature published two papers on bridge editing, the new genome engineering technology from @ArcInstitute: nature.com/articles/s4158…, nature.com/articles/s4158…. I'm quite excited about its potential! Since the whole thing is pretty arcane, I fed the blog post (arcinstitute.org/news/blog/brid…) to Claude 3.5, and asked it to write an introduction. Below is the rather impressive (unedited) result. Genome Design: The Bridge to Our Biological Future I. Imagine you're trying to edit a document, but instead of a cursor, you have a pair of scissors. You can cut out words you don't like, maybe paste in a few new ones, but precise editing? Forget about it. Now imagine someone hands you a pen. Suddenly, you can write whatever you want, wherever you want. This is the kind of leap we're seeing in the world of genome editing. For the past few decades, we've been snipping away at genomes with tools like CRISPR, making impressive progress but always constrained by the fundamental nature of our tools: they cut DNA. But what if we could write directly into the genome, inserting whatever we want, wherever we want, without ever making a single cut? This isn't just a "wouldn't it be nice" daydream anymore. Researchers at the Arc Institute have discovered a new system that does exactly that. They're calling it "bridge recombination," and it might just be the biggest revolution in genetic engineering since CRISPR. II. To understand why this is such a big deal, we need to take a quick tour through the history of genetic manipulation. In the late 1990s, we discovered RNA interference (RNAi). This was our first real taste of programmable biology. We could use short RNA sequences to target and shut down specific genes. It was like having a universal remote control for gene expression. Cool, right? Then came CRISPR in the early 2010s. Suddenly, we could not just turn genes off, but edit them directly. It was like upgrading from a remote control to a basic text editor. We could cut out bad genes and paste in good ones. But there was always a catch: CRISPR works by cutting DNA, and cells don't always repair those cuts exactly the way we want them to. Both of these systems were revolutionary, but they shared a common limitation: they were destructive. They worked by breaking things – either the RNA transcripts of genes (in the case of RNAi) or the DNA itself (in the case of CRISPR). III. Enter the bridge recombination system. The researchers at Arc Institute, led by Dr. Patrick Hsu, were poking around in the genomes of bacteria, looking at transposable elements. These are sometimes called "jumping genes" because they can cut themselves out of one part of a genome and paste themselves into another. They were particularly interested in a group called IS110 elements. These are about as minimalist as you can get while still being functional – just a gene for the enzyme that does the cutting and pasting, plus some mysterious flanking DNA segments. What they found was surprising. When an IS110 element cuts itself out of a genome, those mysterious flanking segments join up to form an RNA molecule. This RNA folds into two loops, one that binds to the IS110 element itself, and another that binds to the target DNA where the element will insert itself. This RNA – which they've dubbed "bridge RNA" – is the key to the whole system. It's like a set of instructions, telling the enzyme exactly where to insert the DNA and what DNA to insert. IV. Now, you might be thinking, "Okay, that's neat, but how is this different from CRISPR?" The key is in how the insertion happens. CRISPR works by making a cut in the DNA and then relying on the cell's repair mechanisms to insert the new DNA. It's effective, but it's also a bit like performing surgery with a chainsaw. Sometimes you get exactly what you want, but often you end up with small errors or unwanted insertions or deletions. The bridge recombination system, on the other hand, doesn't cut the DNA at all. It unzips a small section, inserts the new DNA, and zips it back up again. No broken DNA strands, no relying on error-prone repair mechanisms. It's precise in a way that CRISPR can only dream of. But the real magic is in the programmability. Remember those two loops in the bridge RNA? They can be programmed to recognize any DNA sequence. This means you can tell the system to insert any piece of DNA into any location in the genome. It's like having a word processor for DNA. V. The implications of this are staggering. Here are just a few possibilities: • Gene Therapy 2.0: Current gene therapy approaches often rely on somewhat random insertion of therapeutic genes. With bridge recombination, we could insert corrective genes exactly where they need to go, without risking disruption of other important genes. • Synthetic Biology: Want to give an organism a completely new capability? Just design the gene and insert it precisely where you want it. • Evolutionary Biology: We could insert reporter genes at specific locations across the genome, allowing us to watch evolution happen in real time. • Agricultural Improvements: We could insert beneficial genes into crops with unprecedented precision, potentially revolutionizing our ability to create drought-resistant or nutrient-enhanced plants. • Bioengineering: Imagine being able to design and build entire genetic circuits, inserting each component exactly where it needs to be for optimal function. VI. In the grand scheme of things, the discovery of bridge recombination feels like a pivotal moment. It's as if we've been trying to write the book of life with a typewriter, and someone just handed us a word processor. The researchers at Arc Institute have opened a door to a new era of genome design. As with any breakthrough of this magnitude, it's hard to predict exactly where it will lead. But one thing is certain: the future of biology just got a lot more interesting. As we stand on the brink of this new frontier, I'm reminded of a quote from Arthur C. Clarke: "Any sufficiently advanced technology is indistinguishable from magic." With bridge recombination, we're not just editing the genome anymore. We're writing it. And that, my friends, is pretty close to magic.

The Backlog Of Honolulu Building Permits Is Taking A Toll On City Revenue : Time is money, and it’s not just permit applicants who lose. The city pays a price, too.  dlvr.it/T7wmWw #HInews

Nike staff memo from 1977.

- Almost all data centers around the world will, over time, be powered by AI instead of conventional CPUs. - Compute coming online is increasing 10x every 6 months. Elon Musk on NVDA, @elonmusk

Here is a much longer clip that gives full context into what @ylecun & @DaphneKoller were talking about.

qarbontech.io/products

MUST READ 🙏 Remembering my teacher Charlie Munger - By Li Lu Thursday, November 30, 2023 I was on a business trip in Asia on Tuesday when I got the call from the Munger family informing me that Charlie was in his final hours. I hopped onto the next flight I could find to California, and before departure, was able to talk to Charlie through the help of his daughter. Charlie had largely lost consciousness, but still I could clearly hear him trying to make a sound to acknowledge he had heard me. Upon landing, I learned that Charlie had left us a few hours earlier. I arrived at his Santa Barbara home and had the opportunity to spend cherished time with family members, reminiscing about all things Charlie. Charlie was engaging, humorous and full of wit even at Thanksgiving dinner just a few days ago, family members told me. I visited his home library again. In that very room, exactly 20 years ago, also on a post-Thanksgiving weekend afternoon, following the introduction by our mutual friend Ron Olson, Charlie and I first struck up a deep conversation which ran for several hours. It began an investment partnership that has now endured two decades. Charlie became my mentor, partner, dear friend and above all, life-long role model. I was so deeply grateful that the Munger family made a special arrangement the next day for me to say a proper and private goodbye to Charlie. There, lying quietly with eyes closed, Charlie looked the same as ever, peaceful and sincere with a subtle smile on his face. There was a serenity about him. For a moment, I was reminded of the Living Buddhas I once saw in the Buddhist temples of Thailand. In the Buddhist tradition, the bodies of truly enlightened monks, through life-long self-cultivation, can remain incorrupt, without any traces of mummification after death. In that moment, it is what I saw in Charlie, an enlightened sage with an incorruptible body, surrounded by a glimmer of eternal light. Charlie was not a Buddhist. That vision can never be tested. But it is incontrovertible that his legacy and impact will live on for generations to come. In our capitalist society, where do virtue, moral responsibility, truth-seeking and public service fit in? Charlie Munger answered these questions through his long exemplary life. He insisted on making money in the most morally sound way, entering transactions only when, if positions were reversed, he would comfortably take the other side. He sought worldly wisdom through life-long learning. He guided life with rationality devoid of mental deficiencies such as envy, resentment and self-pity. He faced and persevered through countless adversities with stoicism and equanimity. As he gained in wealth and stature, he showed little appetite for the trappings of that success, and instead spent his wealth on worthy causes and tirelessly spread his worldly wisdom to those who would listen, often with humor. He remained deeply engaged with family, friends, partners and the broader world with loving assiduousness through his last days. In his later decades, Charlie Munger’s ideas began to spread across the world, particularly in the most populous countries of China and India. In China, the Mandarin language version of “Poor Charlie’s Almanack,” an anthology by and about Charlie Munger, sold over 1.2 million copies over the last 10 years. There, the educated class increasingly came to view Charlie as the embodiment of the modern-day Confucianism, maintaining a virtuous and enlightened life while embracing the market forces of capitalism. In time, that vision of modern Confucianism will be crucial for Chinese modernization and how China interacts with the rest of the world. Charlie’s teachings will continue to spread, inspire and impact the world even more profoundly. That will be his eternal legacy. Please retweet

@AdamMGrant @marissashandell Hi @AdamMGrant Apologies - different but perhaps related question. What about Trust? Must it be earned or given and proven right (or wrong) over time? Thank you

Some Honolulu Building Permit Applicants Sailed Through Despite Long Waits For Most: A Civil Beat analysis raises questions about the fairness of wide disparities in how fast permits get approved. dlvr.it/SxdGbp (↓ Click to read) #HInews

thetechcapital.com/global-ai-data…

So much fun to host the inaugural Q Connector™ Podcast Series 🎙️ yesterday with @StructureRes MD Philbert Shih & @qarbontech Founder & CEO Robert Davidson. We discussed #DataCenter infrastructure + orchestration for the #AI age. Watch here >>> youtu.be/p6rQRPvZQSo

literally the greatest performance in any all-star game 3-point shooting contest ever this shit don’t make any sense SHE HIT 25 OUT 27 SHOTS LOL WTF

We are very excited to announce the inaugural episode of the Q Connector™ Podcast Series! On this launch episode we are honoured to host industry heavyweight Philbert Shih - Managing Director & Founder of @StructureRes...// Register Your Place Today! >>> lnkd.in/d3bDjpSK

Shohei Ohtani's night: 2 HR as a batter 10 Ks as a pitcher. 😱

*With complex new requirements driven by digital transformation, #datacenter orchestration is becoming mission-critical for efficient management of data center resources and operations...* // ptc.org/2023/06/delive…

Are you ready to transform an entire global industry? We are currently recruiting for a Product Manager API to join the growing Qarbon team on our mission to revolutionise the way customers interact with their #datacenter infrastructure across the globe..! linkedin.com/jobs/view/3632…

What if automation could keep your #data flowing? Read our launch blog for the new Qarbon Tech Q Blog Series, authored by Qarbon Founder & CEO, Robert Davidson – a series that we are planning to publish monthly with insights from across the tech world...// qarbontech.io/blog/what-if-a…

qarbontech.io/newsroom/teles…

Hydrangeas in the sky in Shizuoka City. Hydrangeas are the symbol of the rainy season in Japan. This year it is expected to last from the end of May until the middle of July #Shizuoka #Japan #travel 📷 Photo by Makoto Hashimuki