Hi friends 👋,

Happy Friday and welcome back to our 133rd Weekly Dose of Optimism. Just a deluge of big, optimistic news to process this week: breakthrough research reports, splashy $500B investments, major crypto deregulation, and not one, not two, but three lunar lander launches. Good news from every part of the universe we cover. We’ll try to weave it all together for you in a way that makes sense. That’s what you pay us the big bucks to do.

Let’s get to it.

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(1) RNA neoantigen vaccines prime long-lived CD8⁺ T cells in pancreatic cancer

Sethna et al in Nature

At an extended 3.2-year median follow-up from a phase 1 trial..., we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P  =  0.007).

mRNYAY!

Researchers have developed an mRNA-based cancer vaccine that generates long-lived, functional T cells targeting pancreatic ductal adenocarcinoma (PDAC). Pancreatic cancer is one of the deadliest cancers, with a 5-year survival rate of only about 12%.

In a phase 1 trial, patients received surgery, a PD-L1 inhibitor, chemotherapy, and a personalized mRNA vaccine. At the 3 year mark, 75% of patients were cancer free. Moreover, responders with vaccine-induced T cells had significantly longer recurrence-free survival compared to non-responders, meaning those that responded to the vaccine went much longer without their cancer coming back than those who didn’t respond.

The research shows the vaccine created immune cells that lasted for years, stayed active against cancer, and could help prevent it from coming back. 85% of vaccine-induced T cell clones persisted for at least two years, with a median lifespan of 7.7 years and some projected to last decades. The T cells maintained strong anti-cancer activity and infiltrated recurrent tumors, meaning they could help control cancer over the long term. The study’s results are extremely compelling evidence that mRNA cancer vaccines can induce durable immunity.

However, the study is not without its skeptics. Vinay Prasad pointed out on X that the study had multiple design flaws and that there have been many promising cancer vaccines, but ultimately only one approved by the FDA. Here’s the hoping Prasad is wrong on this one.

(2) Latest DB-OTO Results Demonstrate Clinically Meaningful Hearing Improvements in Nearly All Children with Profound Genetic Hearing Loss in CHORD Trial

From Regeneron

Regeneron Pharmaceuticals, Inc. today announced updated data for the investigational gene therapy DB-OTO from the Phase 1/2 CHORD trial in 12 children who have profound genetic hearing loss due to variants of the otoferlin (OTOF) gene.

Gene therapy restored hearing. I’ll say it again louder for the people in the back. Gene therapy restored hearing.

Last week, we kicked off the Dose with two gene therapy wins: restoring a blind man’s vision and treating a baby’s spinal muscular atrophy in the womb. Now, another gene therapy restored hearing in deaf children. This is a miraculous trend.

Regeneron's gene therapy DB-OTO showed significant hearing improvements in 10 of 11 children in the trial, with some reaching near-normal levels of hearing. Wild. Here’s how DB-OTO works: the gene therapy uses a harmless virus to deliver a working copy of the OTOF gene into the cochlea, restoring a key protein (otoferlin) needed for hearing. In children with otoferlin-related hearing loss, their inner ear cells detect sound but can’t send signals to the brain due to a faulty gene. By injecting DB-OTO directly into the cochlea, the therapy enables these cells to produce otoferlin, re-establishing sound transmission and allowing children born deaf to hear. Voilà!

Overall the trial not only met but exceeded expectations. Ten of eleven children in the trial experienced significant improvements in hearing. One child, treated at 10 months, demonstrated speech and developmental progress. And best yet, the treatment was delivered in a relatively simple procedure and the children experience only mild and temporary side effects. Hear hear.

(3) Not just for big dogs! Our senior dog program receives preliminary FDA efficacy acceptance (RXE)

From Loyal

This makes Loyal the likely recipient of both the first- and second-ever RXE acknowledgements from the FDA for longevity drug programs for any species — including humans.

Loyal is making some big (and small) dog moves!

The biotech company focused on canine longevity (and R&D that could eventually benefit humans) announced that the FDA granted its drug a “reasonable expectation of effectiveness” in extending senior dogs' lifespans. Loyal still needs the FDA’s final approval before it hits the market, but the company is still targeting late 2025 availability. The drug, called LOY-002, will be offered to senior dogs of all sizes (or at least >14 lbs). Importantly, Loyal’s previous programs focused on older, larger dogs and wasn’t available to smaller and medium sized pooches.

While Loyal can’t really yet make claims on lifespan extension, it does comp the drug to a previous study from Purina on caloric restriction that extended dogs lives 2 years. Dogs can’t be on caloric restriction forever, that’s not sustainable, but taking a beef-flavored LOY-002 drug may be scalable to millions of dogs.

Extending the lives of millions of dogs is a good thing. Achieve that and Loyal is not only a valuable company, but likely a very loved company. But the company’s ambitions don’t stop at dogs. It wants to build on its learnings in creating canine longevity programs to build human longevity programs. And if they achieve that before others, Loyal is likely one of the most valuable and important companies in the world. Bow wow wow.

(4) Arc Virtual Cell Atlas launches, combining data from over 300 million cells

From Arc Institute

The Atlas debuts with two foundational datasets…The first is a new, open source, perturbation dataset called Tahoe-100M, created by Vevo Therapeutics, comprising 100 million cells and mapping 60,000 drug-cell interactions across 50 cancer cell lines. The second dataset, scBaseCamp, is the first single-cell RNA sequencing dataset from public data to be curated and reprocessed at scale using AI agents.

Arc on a bit of a tear recently!

Last week, they released Evo 2, an AI model that learns the “language” of DNA, allowing it to predict the effect of mutations, design new sequences, and influence gene expression.

This week, they released Virtual Cell Atlas, a resource for AI-driven biological discovery, starting with data from over 300 million cells. The Atlas standardizes diverse single-cell data for easier computational analysis, helping researchers study drug responses and disease mechanisms.

The initial release includes two major datasets: Tahoe-100M, mapping 60,000 drug-cell interactions across 50 cancer cell lines, and scBaseCamp, an AI-curated single-cell RNA sequencing dataset spanning 21 species. To gather all this, Arc developed AI agents to continuously collect and process public data, removing the need for manual curation.

Those Collison boys are shippin’! And speaking of the Collisons, Stripe released its 2024 Annual Letter this week — $1.4 Trillion in total payment volume in 2024. Those Collison lads are both shippin’ and rippin’!

(5) Apple will spend more than $500 billion in the U.S. over the next four years

From Apple

“We are bullish on the future of American innovation, and we’re proud to build on our long-standing U.S. investments with this $500 billion commitment to our country’s future,” said Tim Cook, Apple’s CEO. “From doubling our Advanced Manufacturing Fund, to building advanced technology in Texas, we’re thrilled to expand our support for American manufacturing. And we’ll keep working with people and companies across this country to help write an extraordinary new chapter in the history of American innovation.”

$500B! How ‘bout them apples?!

Apple is committing $500 billion to U.S. investments over the next four years, focusing on AI, silicon engineering, and advanced manufacturing. The scheduled investments include a new server manufacturing facility in Houston, expanded chip production in Arizona, and a doubled $10 billion Advanced Manufacturing Fund. The additional investment is expected to add about 20,000 Apple jobs and, in addition, the company is launching a manufacturing academy in Detroit to train workers in AI and automation.

Why would Apple do this? Besides some obvious genuflecting to the Trump Administration, the move to onshore some of its manufacturing infrastructure to the U.S. is intended to increase supply chain resiliency in the face of increasingly cooled relationships with China. And maybe to give Tim Cook a little power back.

A couple weeks ago, on the Shawn Ryan Show, Anduril co-founder Palmer Luckey called Cook out for the company’s (necessary but embarrassing) stance on China:

Like Tim Cook, I have nothing against the guy, personally, but like if I were him, I would feel a little humiliated that I can’t say anything about China despite supposedly on paper being one of the most powerful men in the world.

…He’s politically engaged. Imagine what would happen if he said something like “I believe concentration camps are bad.” Like China, on account of the Uighur Muslim issue, would immediately lock them out of the country. He can’t say that. Isn’t that crazy?

I’ll stop. Palmer keeps going. Watch it. I started the clip at the beginning of the rant.

Critics argue that a lot of this is money Apple was going to spend in the US anyway, packaged into a nice, big, round, Trump-pleasing number. That may be the case.

But Apple is the most valuable company in the world — by a margin of, coincidentally, $500B — and it makes sense for it to continue to invest in its home country, make its supply chains less vulnerable, and (frankly) score a major political win with an administration that values flattery and cooperation above all else. We’ll take the W.

And if you hear Tim Cook start making Winnie the Pooh jokes, you’ll know what happened.

(6) Righting a major wrong

From Coinbase

SEC staff has agreed in principle to dismiss its unlawful enforcement case against Coinbase, subject to Commissioner approval – righting a major wrong. We’ve always maintained that we were right on the facts and the law, and today’s announcement confirms that this case should never have been filed in the first place. This is a victory not just for Coinbase, but for our customers, the United States, and individual freedom.

Big win for crypto!

The SEC has agreed to drop its lawsuit against Coinbase, pending commissioner approval. This case was a particularly frustrating one for anyone involved in crypto —the SEC had previously reviewed and approved Coinbase’s business model when it went public in 2021 but then sued the company in 2023 without any changes to its operations. The case, which was brought forth under Gary Gensler’s SEC, was pretty obviously politically motivated and a blatant example of the the SEC’s broader anti-crypto agenda.

The crypto industry, especially the larger companies like Coinbase, want clear crypto guidelines and regulations — they want certainty that their businesses could not overnight be the target of overreaching and vague regulation. It must be extremely frustrating to run a business that, at any point, could be the victim of politically motivated regulation. The SEC’s dropping of the lawsuit signals that those days of vagueness are over.

(7) Humanity has THREE lunar landers heading to the moon right now

Christian Keil on X

Video from Firefly Aerospace on X

We are so back. Literally. To the moon. Literally. Like “We are so back to the moon.”

As we speak, three private companies—Intuitive Machines, Firefly Aerospace, and ispace—have lunar landers en route to the moon. Until Intuitive Machines’ Odysseus lander touched down near the lunar south pole a year ago, no American craft had landed on Luna since 1972. 1972! Fifty-three years!

Now, in 2025, two American craft and one Japanese are on their way.

1. Firefly Aerospace's Blue Ghost mission, launched on January 15, 2025, is part of NASA’s Commercial Lunar Payload Services (CLPS) program, which wants to establish a steady flow of robotic missions to the moon.

2. Intuitive Machines launched its second lunar lander, IM-2 (Athena) on Wednesday aboard a SpaceX Falcon 9 rocket, heading for a planned landing at Mons Mouton near the moon’s south pole. The lander is mostly carrying equipment use to drill for water ice, some smaller lunar rovers, and some communications equipment. This is also a CLPs program, and along with Firefly, a great example of public<>private<>private partnership between NASA, SpaceX, and Intuitive Machines/Firefly.

3. Japan’s ispace Resilience lander, which also hitched a SpaceX ride on January 15, 2025, is not part of the CLPS program but has been selected for a future CLPS mission.

Today, the moon. Tomorrow? Mars…which may be showing more signs of life than previously thought.

We’re even brining things back from space. Not Boring Capital portfolio company Varda’s W-2 spacecraft “successfully executed its final reentry burn and is preparing to deorbit” and will land in Australia in the coming days. We’ll keep you posted, but in the meantime, please enjoy this shot of W-2 streaking across the night sky.

What a beautiful universe we get to explore.

Have a great weekend y’all.

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Thanks for reading,

Packy + Dan