Comment by adanguyenx | Hacker News Reader

Comment by adanguyenx | Hacker News Reader

For anyone interested in learning more about partial reprogramming, I recently wrote a review article on the current state of the art: https://www.adanguyenx.com/blog/partial-reprogramming

In short, we're still far away from using it in humans (10+ years). Currently, all companies working on this are in pre-clinical stage, with turn.bio as the closest, expecting to go into clinical trials late this year.

This tech is exciting but there are still a lot of limitations:

- Risk of cancer: this technology is based on the work of Yamanaka in 2006, who discovered 4 factors that can turn any cells into pluripotent stem cells. The work in the OP article basically used the same 4 factors, but only partially, so that the cells became "younger" without losing their identities (i.e. turning into stem cells). This requires understanding the right dosage for every cell type so we don't go overboard and turn them into dedifferentiated cells which could lead to cancer

- Cell specificity, microenvironment, etc.: reprogramming is finicky and the right dosage is dependent on the cell type or the environment around the cells. This is important because you have to figure out the right dosage for each cell type so as to avoid cancer

- Delivery: it's easy to deliver gene therapy to skin cells on a dish, not so much to other cell types or organs in the bodies -- that's why we have not seen very impressive results when this is used on live normal mice

This is the kind of thing that could possibly be worth trillions of dollars. This is something that tens or hundreds of millions of people would be willing to pay thousands of dollars per year on. Now that we have some sort of evidence that it’s possible, I wouldn’t be surprised if companies threw billions of dollars worth of research to make it happen, and that could mean getting a product to market sooner rather than later.

> I wouldn’t be surprised if companies threw billions of dollars worth of research to make it happen

Well you are correct. Altos labs (https://altoslabs.com/) is basically every "who's who" in science doing this with billions of dollars. Including Wolf Reik who is featured in the article.

Although I don't think the majority of these companies will go on to make billions selling drugs, I think the past ten years of VC and pharma funding of basic life sciences researches is likely to pay off in many unexpected ways.

The field of molecular biology didn't exist before World War II; after, a number of funding managers at NIH recognized that there was an incipient science to augment biochemistry and other fields, and funded it through places like Rockefeller Institute (https://pubmed.ncbi.nlm.nih.gov/25862750/).

The long term impact of these early scientists and funders who recognized the potential of MB has been enormous; it lead to the discovery of recombinant DNA, and many other important things which produced an explosion of research.

where I drive to work every day, there was only one biotech (Genentech) campus and now there are probably 20-30 different companies with enormous well-outfitted research labs all stuffed into one little corner of South San Francisco. "Overnight", biotech became a huge industry- overshadowed by the enormous tech industry- but in many ways, the "tech" part is ripe for disruption in ways that look just like the tech industry in 1997.

Either way, it will be interesting to see what is the state of the art 30-40 years from now, assuming the research infrastructure continues apace.

> This is the kind of thing that could possibly be worth trillions of dollars.

I think it would also have a profound impact on society and culture. Just how we think about the world differently as our lifespan extends. I think that makes a lot of people scared.

Discussing this with others I see a few things people are highly concerned with but I'm unsure if they would actually happen (as in, I'm uncertain either way). The first is over population. The reason I'm not convinced this would be a problem is that most western countries have declining populations (without immigration) and world wide we've seen dramatic reductions in birth rates. World fertility rate is about 2.4 (replacement level is 2.0)[0]. The other aspect is political. People think change happens on the generation level. But I'm not entirely convinced of this either. We can take attitudes of same sex-marriage as an example[1][2]. A generation is 20 years but our (US) views have changed substantially faster than that. Especially if you include LGBT[3] (I couldn't find timeline sources for European attitudes as easily. Even when looking for specific countries and including quotes). I agree that there's a correlation with generations, but I'm not convinced it is a principle component.

I also wonder how we would think about the future. Interesting to be is that a lot of Eastern cultures typically are more future oriented in their thinking (as compared to typical Western, and I wouldn't say by too much). I would expect that longer lifespans would put pressure to be more cognizant. Would a crisis that is 100 years out seem as far away? Hard to say. We might even have to live with longer lifetimes for awhile for that to happen.

All I know is that it would cause big changes. But I'm not sure that should stop us from pursuing this technology unless we see major pitfalls ahead of time and find that they are insurmountable obstacles to overcome. There are clearly issues with increased longevity (especially the disproportionate use of it) as many dystopian SciFis have pointed out. But I think it is better that we at least discuss these things in the open since the technology itself is no longer in the realm of fantasy but has graduated to the realm of possibility. There's too much money being put in this technology now for us to not take the questions of the impact of it seriously. Even if 10+ years out (even 50+) I don't think we should dismiss them. If we're talking about culture shifts, maybe one of the best things we could do is talk about the impacts (pros/cons and how to use them in fair and equitable means) of technologies before they are here. Maybe we could have some of that discussion here?

I'm normally not a big CGP Grey person, but I do like this video on the Fable of the Dragon Tyrant[4]

[0] https://data.worldbank.org/indicator/SP.DYN.TFRT.IN?location...

[1] https://news.gallup.com/poll/350486/record-high-support-same...

[2] https://www.pewresearch.org/religion/fact-sheet/changing-att...

[3] https://news.gallup.com/poll/1651/gay-lesbian-rights.aspx

[4] https://www.youtube.com/watch?v=cZYNADOHhVY

In the movie In Time, people trade time instead of money. (money collapsed after the invention of this tech) Work well and you get extra “life” through a device in your arm. So everyone is perpetually 25.

It’s an interesting exploration of the topic.

> people would be willing to pay thousands of dollars per year on.

To note, a huge market segment is are already paying thousands of dollars per yer, right now, on skin care (for instance the SK-II lineup sells well, and it’s 100-250$ a bottle)

My semi-cynical view would be that cosmetics companies don’t have any specific incentive to accelerate the natural march of research as long as they stay on the forefront of it and have top of the line products. Basically they’d only have issues with new players making bolstering entrances and disrupting their market with a revolutionary products they’re not ready to counter.

And the gap between some process being validated, and a product with that process being on the market is so huge, it’s hard to see a non entranched company start investing on that without getting noticed.

I’d see it as the same situation as Camera makers when digital was coming at the horizon. They only needed to be there when the tech is ready, and had no need to bet the farm on making it a reality sooner than necessary.

> I’d see it as the same situation as Camera makers when digital was coming at the horizon. They only needed to be there when the tech is ready, and had no need to bet the farm on making it a reality sooner than necessary.

I kind of hate to say it, but isn't this why patents exist? The first company to make a product with this tech will have exclusivity for 20 years. Shouldn't that be a sufficient incentive?

Patents only cover processes I think ?

For instance Kodak was first on the ground with their digital camera, but we all know how it went. The same way pharmaceutical companies patent drugs but it doesn’t stop a rival company from doing their own development cycle and coming up with a competing drug based on the same molecule.

Patents cover devices too. The cotton gen, dish washer, and toilet paper holder were a patented at one point.

It's a demonstration that the modern patent system fails at that.

I think if patents worked like that, there'd be a thriving market for patents on emerging technologies. VCs would fund research groups to do basic science, and their deliverables would be successful experiments and prototypes, turned into patents.

Instead, patents are used defensively, for obvious things and rent-seeking. Why is that?

I'm not sure, but I can imagine a combination of:

* You don't have to prove your invention works.

* Patents can be vague and broad, and the non-obviousness bar is depressingly low. Low effort patents have more power than real advances.

* It's hard to enforce patents on in-house processes and systems.

* Workarounds can be found after you've done the hard work.

* Basic research (e.g. algorithms) can't be patented, and basic research is the hardest part.

We really do need a system that makes basic research with high eventual impact profitable. Brilliant scientists are getting paid peanuts.

I'm trying not to show my ignorance by saying something terribly wrong, but my sense is that the patent system works better in pharma than in software. Pharma companies don't need to patent algorithms, but—this is where I hope I'm not saying something wrong—I think they can patent e.g. molecules?

Certainly, the first company to the market with a drug is usually rewarded pretty heavily, until generics come online 20 years later.

they can patent molecules and synthetic routes. but once one company shows that targeting a particular receptor works, or binding to some site on a protein, other companies can find drugs that so the same thing but look different.

for instance, Prozac was a breakthrough (the first SSRI), but it was easy for other companies to make their own SSRIs.

> cosmetics companies don’t have any specific incentive to accelerate the natural march of research as long as they stay on the forefront of it

This is where the "competition" pillar of capitalism comes into play. All producers would naturally benefit from being a cartel, but in practice the benefit to the One Player Who Cheats (in this case, by developing better products) is so large that we end up advancing anyway.

I see it as the same dynamic we have in bike races.

There’s a peloton running ahead, and they want to keep a sane distance from the pack. They’ll watch and react to the pack getting closer, but won’t be sprinting their lungs off until any of them gets in reaching distance of the goal.

Except when one of them decide to take the gamble (“cheat” as you say) and start sprinting. But we can agree it is extremely rare to have a sole sprinter leave the peloton mid-race and stay ahead until the end.

When it comes to huge international companies with billions and billions on the line, I expect even less of them to make huge gambles and try escaping the peloton with no goal in sight for the next 15~20 years.

Do telomeres and telomerase play a role in this new discovery?

Telomeres are the ultimate clock for cells that differentiate.

Using your peleton example, there was also that 2020(2021) Tokyo race where the woman just got out in front, maintained the same speed as the trailing peleton (slowed in the 2nd half) and just stayed out of sight the whole time. I guess there were 4 or 5 members of the break out group earlier, but all the others fell back at the halfway mark. Sometimes just getting out front and maintaining speed just works, especially if there's one giant gold everyone is competing for at the end.

> I’d see it as the same situation as Camera makers when digital was coming at the horizon. They only needed to be there when the tech is ready, and had no need to bet the farm on making it a reality sooner than necessary

I'm not so sure this was really true. For example when the mirrorless transition happened Sony had basically bet the farm on making it a reality and as a result they dominate the mirrorless space in marketshare. If a new product is sufficiently better than existing ones then it can overcome the capital advantages of existing players. Especially with modern day VC funds pumping billions into high growth startups.

I also think you have to consider that very few people in legacy companies have cutting edge expertise. Walmart is not going to have the calibre of robotics, AI, or engineering personnel that Amazon does.

I think Sony didn't gamble that much on mirrorless, and were already in a good position to make it happen.

They had a CCD/CMOS group company since the 80s and started using them in video cameras. From there they also produced sensors for feature phone, smarphones, and mirrorless was more or less an extension of that

> My semi-cynical view would be that cosmetics companies don’t have any specific incentive to accelerate the natural march of research as long as they stay on the forefront of it and have top of the line products

I looked at the Linkedin information for a few cosmetic companies and found that most of the employees work in marketing and channels, followed by business administration, and followed by a handful of cosmetician. My guess is that either research and development are outsourced or they are primarily marketing companies, which means there might not be any research to begin with.

They have found that it absolutely doesn't matter how well, or if, the products work. It suffices to suggest they might.

If somebody came up with a product that actually did work, they know they would be in deep trouble.

https://en.m.wikipedia.org/wiki/Trouble_with_Lichen by John Wyndham,1960

I wouldn't go that far as say there is absolutely no research at all; however, I saw several articles debunking the claims by manufacturers regarding the efficiency of these products. Basically, there are the equivalent of vitamin supplements: by now everybody should know there is no benefit in taking them if you have no specific deficiency but the market is still huge and people seem to buy them indiscriminately.

The reason for this is simply sad. Imagine you are a woman in your forties, fifties and so on. For your whole life the society was communicating to you in different ways, directly and indirectly, that a large share of your value lies in your beauty. Now it is fading away and there is no going back. So you do what you can to slow this process down. If you believe it works, you simply feel better. And when you tell it to your friends, of course they will support you ("This cream really works miracles, you look so much younger"). Same with cosmetic surgeries, for some people it verges on the bring of psychiatric disorder, with one operation after another turning you into a monster, but when you look into the mirror you perceive yourself as more beautiful than before.

>For your whole life the society was communicating to you in different ways, directly and indirectly, that a large share of your value lies in your beauty

Is this really still true? I know of many female professionals who are respected for their skills alone

This is great and as it should be, but I don't believe it applies to the society at large.

If you think any societal bias you have heard about has disappeared, you will generally be disappointed.

The societal biases that disappeared are almost excluse those that are so long gone that we have little chance to even know they existed.

From what I can see from the outside as a man, even successful female professionals are expected to _look_ like a successful female professional, which is thin, elegant, classy, with a good amount of make-up. A huge part of the perception of how successful female professionals are comes from their looks.

I notice that this beauty standard is mostly kept alive by women themselves. Men care a lot less about the appearances of professionals, especially if they're women. It also depends on the industry. Women in engineering seem only really to be judged by other women outside of engineering. Maybe this is why you haven't noticed it?

Isn't LinkedIn also just much more useful for marketing people while r&d employees don't need to care for it as much (and sometimes don't even do the work under the parent company in the first place)?

> To note, a huge market segment is are already paying thousands of dollars per yer, right now, on skin care (for instance the SK-II lineup sells well, and it’s 100-250$ a bottle)

Side question: do these skin care products work? Is anyone here on HN using them and notice any difference?

Retionoids/retinols, sunscreen, vitamin c.

Those are the big three that dermatologists will recommend that have evidence of efficacy for anti-aging.

Anywhere to find cheap versionsv

Retinoids: your doctor

Everything else: The Ordinary

A lightly acidic lotion with sunscreen everyday since late teen years and my skin looks like my late twenties in my early 40s.

Lotion in general does a huge amount to help skin stay healthy and accumulate less exposure damage over the decades.

Suppose a company that currently sees $0 from skincare market wants to have 90% marketshare in skincare in short order.

> I’d see it as the same situation as Camera makers when digital was coming at the horizon. They only needed to be there when the tech is ready

One of the biggest investors in digital photography was Kodak, because they recognized the threat to their film model. Now they used their patents to stall the conversion to digital instead of using their lead to dominate a new market, but it's not uncommon for companies to invest hard in their replacement to secure IP. That's why MS was getting paid $5/android phone for a while.

And that is why nobody wants to find the truth, that the effects are human caused, and not natural.

You'd think that, but it's 2022 and they haven't found a decent solution to male baldness.

Rogaine and off-label finesteride don't quite cut it.

There are quite a few solutions, but you won't like any of them.

The basic issue is, and remains, that certain cells die the more and the longer they're exposed to DHT. To solve male pattern baldness, you'll have to reduce your DHT levels, either by reducing your testosterone levels, or by taking brutal dosages of finasteride.

Trans women actually do that, and can stop and even reverse male pattern baldness most of the time. But for cis men, this solution is obviously inadequate.

Does taking fin reduce test and thus muscle gain? I’ve read it reduces sex drive

I'm sorry, I honestly don't know, I never had a need for it. You might want to ask in the corresponding boards on Reddit, though.

I am of the opinion that the elite top 0.1% would intentionally hoard this and make it out of reach of even your standard rich person. I don't think they would allow this tech to spread such that ordinary people could get their hands on it.

Ah, American thinking? Just go to Asia, every medicine on the planet is copied there and sold cheaply at pretty much any pharmacy.

And what percentage of the time is is medicine free of nasty additives? As opposed to labeled sugar pills. Or heck, how there are cases of lead in paint still.

All evidence points to the contrary. We have OTC drugs, or relatively accessible prescriptions, that already expand health and lifespan drastically - otherwise we'd all be dying young.

I don’t think anyone physically could horde it for even as long as 20 years no matter how hard they tried. Tech has a way of diffusing rapidly — things that start off only affordable by the richest yuppies of Wall Street and London can be superseded by street-wares in Nairobi, and this is not limited to just computers and phones, for example one of the YouTube channels I follow genetically engineered yeast to produce spider silk: https://youtu.be/2hf9yN-oBV4

Is there any precedent of any medical technology hoarded by the 0.1%?

I don't think so. Once something is out and proven to be cost-effective, even expensive treatments, it proliferates into the top 5-10 per cent of the world's population pretty fast.

So Peter Thiel and Putin will live forever ..

The business of deaging would have interesting implications on society as a whole as well if people suddenly started living an extra 30 years.

Only 10ish years? This is incredible news.

Shit man I might even be alive by then

HahahahHHAHAHAHAHA

I love your username too.

Hey I maybe maybe might be alive by then too! Who knows.

There's life after death.

So, before full self driving then!

Self driving is easy, the hard part is self driving when surrounding vehicles are driven by humans. There are self-driving trains in some subway systems right now, and we don't see those as something special.

It's not just about handling human drivers. There's also pedestrians, construction areas, weather, various other kinds of obstructions, hardware failures...

I think the interesting question is, in a future where death is no longer inevitable, what risk profile we would accept for self driving? Would it accelerate self driving, or get rid of cars altogether?

Like fusion and self driving cars. It is going to take a lot longer if it ever works safely.

Neither fusion nor self-driving cars are a vital technology, they are more like "nice to have". You can produce electricity by many other means and people are used to driving.

But preventing aging isn't yet possible, so there is more sense of urgency around developing anything that helps.

Given the looming aging crisis in west and east i would expect vigorous interest in bringing this science closer. Not least because it is presumed that it would also solve many aging related diseases like Alzheimer's

I've got a bridge to sell you!

That post is beyond incredible.

Thanks for compiling and condensing all the information into a blog post.

Thank you for the context. Do you have any recommendations as to where I can learn more about the state of the art in this space?

10+ years is far away? That sounds like right around the corner!

Can you "de-age" organs and things that will actually keep us alive. I don't care so much about my skin.

It might not be the most vitally important but ignoring the single biggest organ we have seems like a mistake to be honest.

Skin is vital, as you need to deage veins.

We'd probably be able to grow and transplant bespoke organs for you before then.

Aging is a complex process. Do not ignore something as big and heavy as skin. It is entirely possible that secretions from aged skin cells dysregulate other organs etc. Given that we have been judging a person's health by their skin for centuries, it probably reflects the internal state of the organism somehow.

Perhaps a side effect of this may be a better understanding of cancer… or new treatments …

Reply on news.ycombinator.com