Retro: A longevity biotech triple-threat?

Joe Betts-LaCroix on investing in longevity biotech and Retro’s progress in cellular reprogramming, autophagy and plasma programs.

When longevity-focused decentralized science platform VitaDAO recently announced its latest funding round, one of the participants in the round was Retro Biosciences founder Joe Betts-LaCroix. A serial entrepreneur and investor, Betts-LaCroix founded Retro in 2021 to develop cellular reprogramming, autophagy and plasma-inspired therapeutics, with the goal of increasing healthy human lifespan by 10 years. Last year, the company announced it had secured funding of $180 million from an undisclosed source, revealed last week to be Sam Altman, the CEO of OpenAI. 

Longevity.Technology: A former Harvard, MIT and Caltech scientist, Betts-LaCroix was the founder of OQO, which created the world’s smallest Windows computer and was ultimately sold to Google. Since then, his focus has been largely on health-related ventures and investments, including founding research automation company Vium, which was sold to Recursion Pharma in 2020. So, what is it about longevity that makes Betts-LaCroix tick as both a founder and an investor? 

After the sale of OQO, Betts-LaCroix says that “he tried to retire” but quickly realized this wasn’t going to work for him.

“I got myself onto a tropical beach and I looked at the sunset for about 10 days, it was pretty chill,” he recalls. “But then I thought it was just too boring and too sad to sit here doing nothing and getting older year after year.”

Why focus on longevity biotech?

Reflecting on his success at OQO, Betts-LaCroix says that the venture was ultimately “cool, but kind of hollow.”

“So that got me wondering what my next venture would be – could it be something that I’d look back on in years to come and not feel cynical about it?” he says. 

To try and find an answer to this question, Betts-LaCroix describes a thought experiment where he imagined advanced aliens observing humanity and our progress: 

‘Okay great, they’re heading towards space, but have they figured out what they’re made of yet, have they mastered their medium? Nope. They haven’t got a clue. They don’t know why it breaks. They don’t know how to modulate it.’  

There on the beach, Betts-LaCroix decided that understanding human biology and aging is what he wanted to focus the rest of his career on. 

“In a pragmatic sense, it’s also important if we’re spending 85% of our healthcare dollars, which is already a big portion of our GDP, on diseases of aging,” he says. “I think part of the big thesis behind the longevity biotechnology industry in general, certainly for Retro, is that aging biology offers a different approach to looking at age-related diseases, and that there’s an upstream cause that can be addressed therapeutically.” 

The longevity sector’s more “upstream” approach to treating age-related disease is, says Betts-LaCroix, also a source of many unique therapeutic targets. 

“It means a company like Retro can walk into a green field of potential targets that haven’t been addressed by this disease-focused industry that’s been operating over the last 100 years or so,” he says. “The hypothesis is that there are fewer aging mechanisms than diseases of aging. Therefore, intervening in one hallmark of aging will probably ameliorate or prevent multiple downstream age-related diseases.”

Investment philosophy

His recent investment in VitaDAO is a testament to Betts-LaCroix’s interest in the unknown aspects of human biology. 

“I like it when I see people doing things differently, experimenting with things,” he says. “It signals that the lights are on somewhere – you have people willing to take risks, rethink something from the ground up, reapproach something from first principles. So, the fact that VitaDAO is taking a fresh look at aging, and thinking about how we use some of this energy to help solve age-related disease, is very appealing to me.”

VitaDAO is also “stage-matched” to Betts-LaCroix’s taste as angel investor. 

“I like to get involved in things that are what they call ‘deep tech’ in Silicon Valley VC circles – where you get to play with the actual mechanisms of how things work,” he says. “Longevity biotechnology is still at a stage where it’s all about basic biology. How does aging work? There’s a lot that’s still to be figured out.”

‘Invest in things you understand’

Betts-LaCroix admits that the fundamental work that needs to be done in aging is not a typical area for investors to get involved in. 

“Most investors are looking for the shortest path between dollars and dollars prime, and the least amount of risk,” he says. “And it’s a quite rational strategy to invest in things that they understand. It’s a lot easier for someone to invest a large amount of money into Coca Cola, say, because they understand the business model, they’ve seen the development over the last numerous decades of how it unfolds, and what dividends it pays.”

But this is also why Betts-LaCroix feels comfortable investing in the longevity field. 

“I have an advantage in that I’ve been paying attention to the academic field of aging biology for over a decade in a fairly active way, so it doesn’t feel alien to me at all,” he says. “You’ve got to invest in things you understand. So, I’ve generally limited myself to investing things that involve molecules and preferably as close to aging biology as possible.”

Avoid one-bucket thinking in aging

But Betts-LaCroix clarifies that investing in what you understand doesn’t mean investing in one thing. Especially when it comes to aging.

“People easily fall into this ‘one bucket’ thinking where they identify one thing as the cause of aging,” he says. “And they just freak out about it – ‘we’ve discovered the cause of aging, it is X’ – where X is a single thing. And people have done that many times.”

“And that’s kind of sad to me. I think it’s distracting because they’re saying, ‘don’t waste your effort on these other things, invest in my thing,’ it’s a promotion mechanism. As a student of aging biology and having looked at hundreds of papers on the topic over the years, it’s clear to me there are multiple things going on in parallel. And anybody who stands up and says the cause of aging is negative factors of blood or telomeres, or histological entropy caused by a genetic noise or whatever is probably a salesman.”

This thinking is largely behind Betts-LaCroix’s decision to make Retro a multi-program longevity company.

“Around 90% of clinical trials fail, and probably a similar number of startups often don’t work out – it’s a risky space,” he says. “I could have picked a single mechanism and gone after it, but biology is hard and playing that out will take many years. I’ve come to the stage of my life where I want to do a bunch of things in parallel. And so, as long as I can partner with brilliant people who have the capability to execute that, and the resources to do it, then why not?”

Heading into the clinic

Switching to progress at Retro since it unveiled, Betts-LaCroix says that the company expects to have its first ‘clinical event’ this year in its autophagy program.

“We have a lead, and we’re also ramifying that lead into a bunch of expanded indications and expanded compounds – with enhanced pharmacological properties and so on,” he says. “The kind of autophagy that we’re working on is specifically around enhancing the degradations of crap that has accumulated and that isn’t specifically of some complex signaling network or pathway.”

With Retro moving into its first clinical phases, the company has also moved to bolster its team with the appointment of biopharmaceutical veteran Guoxian Wu to lead its early drug development team. 

“At Retro, we’ve been primarily hiring brilliant academics – people who are in the very early mechanistic stages of understanding and exploring the biology,” says Betts-LaCroix. “But we’re all headed to the clinic – our purpose is to create therapies for humans – so it’s great to have someone here who makes that later stage feel like less of a mystery. Guoxian has the most experience of anybody here of bringing molecule after molecule after molecule to the clinic.”

Plasma trial under way

When it comes to Retro’s work in plasma-based therapeutics, Betts-LaCroix reveals that the company is already engaged in a clinical trial. 

“To be clear, we’re not doing the sort of the classic bad sci-fi novel approach of connecting young people’s circulatory systems to old people,” he says. “This is all about creating something that billions of people can benefit from and that is implicitly affordable. Our mission is to extend healthy human lifespan by 10 years, but that doesn’t mean extending the life of one rich dude, it means doing it for a broad swath of humanity.”

The specific details of Retro’s plasma program is unclear, but Betts-LaCroix admits the program is “inspired by” the work of UC Berkeley professors Irina and Michael Conboy, whose work indicates that it could be factors in old blood, rather than something in young blood, that potentially holds one of the keys to rejuvenation.

“I think most of the work that people have done inspired by parabiosis is on this fountain of youth, what are the magic elixirs, what are the youth factors? – they want to take that good stuff from the young and plug it into themselves,” he says. “The inspiration from the Conboy’s experiment was that there are clearly some negative factors in old circulatory systems that make a difference.”

Taming the raw power of reprogramming 

The third and final prong of Retro’s three-pronged approach to aging biology is cellular reprogramming. This fascinating area of longevity research has been the subject of much attention, especially since the emergence of Altos Labs and its $3 billion war chest. 

Retro has scored something of a coup in the field by securing the services of University of Lausanne professor Alejandro Ocampo on the company’s scientific advisory board. Ocampo is a recognized leader in epigenetic reprogramming, particularly for his 2016 Cell paper that demonstrated in vivo improvement of aging hallmarks in mice using cellular reprogramming.

“Reprogramming is so big, I have a feeling there’s probably going to be another Nobel Prize in it at some point [Prof Shinya Yamanka already received a Nobel Prize for his work in this area],” says Betts-LaCroix. “But we’re still in the very beginning. I feel lucky to be working in an area of biology where we’re still learning how to tame its effect – it’s so powerful.”

In comparison with other aging interventions, such as metformin, where studies are looking for very small, incremental improvements in healthspan and lifespan, Betts-LaCroix says that the potential for cellular reprogramming is on another level.

“Reprogramming is something where, if you leave it turned up too high, it just completely resets the organism, the whole thing shuts down and turns into a pile of protoplasm. The effects on mice are huge, across all different tissues, and different mechanisms, different aging hallmarks. It’s really exciting to be involved in something where the challenge is, just taming it, making it safer, making it more targeted. It’s just a very exciting space to be in.”